Abstract
Cyclophilins belong to the superfamily of peptidyl-prolyl cis/trans isomerases (PPIases, EC: 5.2.1.8), the enzymes that catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds in unfolded and partially folded polypeptide chains and native state proteins. Cyclophilins have been extensively studied, since they are involved in multiple cellular processes related to human pathologies, such as neurodegenerative disorders, infectious diseases, and cancer. However, the presence of cyclophilins in all domains of life indicates a broader biological importance. In this mini-review, we summarize current advances in the study of microbial cyclophilins. Apart from their anticipated role in protein folding and chaperoning, cyclophilins are involved in several other biological processes, such as cellular signal transduction, adaptation to stress, control of pathogens virulence, and modulation of host immune response. Since many existing family members do not have well-defined functions and novel ones are being characterized, the requirement for further studies on their biological role and molecular mechanism of action is apparent.
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Introduction
Cyclophilins, FK506-binding proteins, and parvulins, collectively referred to as PPIases, catalyze the slow interconversion between the cis and trans isomers of the N-terminal amide bond of the amino acid proline, which often represents a rate-limiting step in biochemical reactions (Wang and Heitman 2005). The first discovered cyclophilin was of mammalian origin, and it catalyzed the interconversion of the cis and trans conformers of the peptide bond preceding a proline residue while it was also the intracellular receptor for the immunosuppressive cyclosporin A (CsA) (Fischer et al. 1989; Takahashi et al. 1989). Since then, extensive structural and functional study on human cyclophilins has shown their involvement in many biological processes, including protein folding and trafficking, while their association with various pathological conditions, like cancer, neurodegenerative disorders, and viral infections, has led to the design of selective drugs with possible therapeutic applications (Davis et al. 2010; Nigro et al. 2013; Schiene-Fischer et al. 2013; Blair et al. 2015; Hopkins and Gallay 2015).
Genome wide analyses have shown the ubiquitous presence of cyclophilin genes in all living organisms, but the number of genes in different organisms varies significantly; usually, eukaryotes encode numerous cyclophilins, whereas prokaryotes only a few (Wang and Heitman 2005). The identified cyclophilins are either small single-domain proteins or large multi-domain ones that contain one or more additional unrelated domains (Pemberton 2006; Krücken et al. 2009). Cyclophilins participate in the folding of newly synthesized proteins and induce conformational changes in mature ones (Schiene and Fischer 2000; Schiene-Fischer et al. 2013). They are involved in various cellular processes, such as signal transduction, stress response, and cell growth and death, and they have been related to pathogens virulence (Ünal and Steinert 2014; Bukrinsky 2015; Gutiérrez-Aguilar and Baines 2015; Ratajczak 2015; Vasudevan et al. 2015; Geisler et al. 2016). This mini-review focuses on microbial cyclophilins and their multitude of functions, which renders them intriguing enzymes awaiting further investigation.
Cyclophilin gene distribution among microbes
Bacteria usually possess only a few cyclophilin genes, some of which show high similarity to eukaryotic homologues (Hayano et al. 1991; Göthel et al. 1996; Manteca et al. 2006). Fungi and Apicomplexa parasites possess more cyclophilin genes, similarly to higher eukaryotes (Pemberton 2006; Krücken et al. 2009). Cyclophilins have also been identified in Dinoflagellata, oomycetes, archaea, and viruses (Nagashima et al. 1994; Gan et al. 2009; Ponmani et al. 2015). Many microbes contain a novel group of PPIases that are characterized by simultaneous existence of a cyclophilin and an FK506-binding domain in the same protein (Adams et al. 2005; Barik 2017).
Cyclophilin protein structure and prolyl isomerase and chaperone functions
Most microbial cyclophilins, of those whose structure has been solved so far, are monomeric and characterized by the presence of a fold that is formed by one β-barrel with eight antiparallel β-strands and one α-helix at each side, showing high similarity to the prototypic member of the cyclophilin family, the human CypA (Clubb et al. 1994; Edwards et al. 1997; Christoforides et al. 2012; Trivedi et al. 2013b). The presence of minor and major variations of this fold, such as insertions, large extensions, dimerization by 3D domain swapping, and divergence of the active site (Henriksson et al. 2004; Limacher et al. 2006; Thai et al. 2008; Ulrich and Wahl 2014; Jakob et al. 2016), suggests diverse physiological functions. For instance, the recently characterized AquaCyps fold into two domains, and they differ regarding their oligomerization state, even though they show major structural similarities. Furthermore, they utilize distinct sets of active site residues, which is consistent with differences in catalytic efficiency and substrate specificity (Jakob et al. 2016).
The initial function attributed to cyclophilins was participation in protein folding. Even though the mechanism is still under investigation, it is assumed that they accelerate the spontaneous prolyl isomerization by lowering the free energy barrier via preferential binding to and stabilization of the transition state configuration of the substrate (Ladani et al. 2015). The thermophilic GeoCyp has been used for studying the role of protein motions in substrate recognition and catalysis (Holliday et al. 2015), and it showed remarkable similarity for in vitro binding and catalytic functions to the prototypical human CypA (Eisenmesser et al. 2005; Doshi et al. 2012).
Many cyclophilins possess chaperone activity (Dimou et al. 2011; Zhang et al. 2013; Pandey et al. 2016), which in some cases is independent of the prolyl isomerase activity. For instance, Leishmania donovani CyP2 disaggregates adenosine kinase complexes by an isomerase independent chaperone function (Chakraborty et al. 2004; Mukherjee et al. 2013), and yeast Cpr7 enhances [Ure3] prion fibrillation independently to its prolyl isomerase activity (Kumar et al. 2015). Furthermore, the negative effect of the cytoplasmic cyclophilin of Escherichia coli on biofilm formation and swarming and swimming motility depends on its prolyl isomerase activity only in the first two instances (Skagia et al. 2017a).
Cyclophilins and CsA sensitivity
The study of microbial cyclophilins enabled the understanding of the immunosuppressive mechanism of action of CsA, which expanded the field of organ transplantation (Tropschug et al. 1989; Liu et al. 1991a). CsA also has antifungal activity mediated by inhibition of calcineurin by the cyclophilin-drug complex in a way essentially identical to its immunosuppressive action (Breuder et al. 1994). Recovery from the division arrest induced by the mating pheromone is sensitive to CsA (Foor et al. 1992). Protozoan parasite cyclophilins have been implicated in the antiparasitic activity of CsA (Bell et al. 2006; Yau et al. 2010). Although bacterial cyclophilins are less sensitive to CsA (Liu et al. 1991b; Compton et al. 1992), a few enzymes with higher identity to eukaryotic homologues show CsA binding and inhibition (Pahl et al. 1992; Göthel et al. 1996).
Multiple roles of cyclophilins in microbial cellular physiology and stress tolerance
Prolyl isomerases show greater specificity for their protein targets than other chaperones, and even though many cyclophilin interaction partners have been identified, the functional significance of the interaction is not always clear. Certain proteins, like DnaK, Pta, and AccC, interact with the cytoplasmic cyclophilin of Azotobacter vinelandii (Dimou et al. 2011, 2012a, b). In yeast, Cpr3 accelerates protein refolding after mitochondrial import (Matouschek et al. 1995), and Cpr6 and Cpr7 interact with the intact ribosome (Tenge et al. 2015). Neurospora crassa CyP40-type cyclophilin binds to a growth and thiamine regulated protein (Faou and Tropschug 2003). Plasmodium falciparum cyclophilins interact with the HSP70 (Leneghan and Bell 2015), and a Trypanosoma brucei cyclophilin associates with a protein involved in ribosomal RNA maturation (Droll et al. 2010). Mycobacterium tuberculosis PpiA interacts with a number of host substrates involved in iron storage, signal transduction, and immune responses, probably acting as an effector mimic of host cyclophilins (Bhaduri et al. 2014).
Expression of many cyclophilin genes is induced in response to various stresses, such as cold and heat shock and antibiotic, antiparasitic, pharmaceutical, and pollutant treatment, suggesting a possible function in stress tolerance (Graumann et al. 1996; Iida et al. 1997; Joseph et al. 1999; Kim et al. 2011; Ponmani et al. 2015; Singh and Dubey 2016). A range of microbial cyclophilins in bacteria, yeast, human cell lines, and plants improves the survival under stress (Kim et al. 2010a, b, 2017; Trivedi et al. 2013a, b; Rêgo et al. 2015; Pandey et al. 2016; Thomloudi et al. 2017). Furthermore, disruption of Saccharomyces cerevisiae CYP1 decreased the survival of cells after heat shock (Sykes et al. 1993), and disruption of L. donovani CYP40 resulted in reduced virulence due to defects in stress resistance (Yau et al. 2014, 2016). In Trypanosoma cruzi, the mitochondrial TcCyP22 cyclophilin is involved in the regulated cell death induced by oxidative stress (Bustos et al. 2017).
Several studies with bacterial cyclophilin mutants suggest that cyclophilins are not essential for growth, since the deletion strains display no distinct phenotype under standard growth conditions (Herrler et al. 1994; Kok et al. 1994; Kleerebezem et al. 1995; Pissavin and Hugouvieux-Cotte-Pattat 1997; Trémillon et al. 2012). The only cyclophilin that it has been suggested to be essential for bacterial growth is rotA from Synechococcus sp. (Hassidim et al. 1992). There are some studies, however, that propose a role for bacterial cyclophilins during special growth conditions. In E. coli, deletion of the cytoplasmic cyclophilin ppiB eliminated growth inhibition by a putative growth inhibitor from the T7 bacteriophage and also resulted in increased motility and biofilm formation ability (Molshanski-Mor et al. 2014; Skagia et al. 2016). In addition, either deletion or overexpression of E. coli ppiB resulted in mild or severe cell filamentation, respectively, suggesting a role for it in cell division (Skagia et al. 2017b). The cytoplasmic PpiB deletion mutant of Legionella pneumophila exhibits reduced growth at 17 °C and attenuated invasion of Acanthamoeba castellanii (Schmidt et al. 1996; Söderberg and Cianciotto 2008).
The eight cyclophilins of S. cerevisiae have non-essential functions probably mediated via regulation of a few unique partner proteins (Dolinski et al. 1997). Cpr1 is implicated in sporulation, where it governs the meiotic transcriptional program (Arévalo-Rodríguez et al. 2000; Arévalo-Rodríguez and Heitman 2005); nuclear export of the zinc-finger-containing Zpr1p protein (Ansari et al. 2002); and the function of Vid22p in the import of fructose-1,6-bisphosphatase into intermediate transport vesicles (Brown et al. 2001). Cpr6 and Cpr7 interact with and regulate the activity of the Hsp90 chaperone (Duina et al. 1996; Tesic et al. 2003), and Cwc27 has been identified within the essential Myb-related Cdc5p complex, which has been implicated in pre-mRNA splicing (Ohi et al. 2002). In addition, Cpr7 inhibits the replication of Tomato bushy stunt tombusvirus by binding to the RNA-binding domain of the replication protein p33 (Lin et al. 2012). Schizosaccharomyces pombe Cyp2 interacts with the SNW/SKIP transcription co-regulator Snw1 (Skruzný et al. 2001). Overexpression of Podospora anserina CypD results in accelerated ageing due to increased autophagy-dependent degradation of mitochondrial and cytosolic proteins (Brust et al. 2010; Kramer et al. 2016).
Particular roles of cyclophilins in microbial pathogenesis
A possible function of microbial cyclophilins in host infection was suggested in several gene expression studies that have shown upregulation of the expression of various cyclophilin genes during infection (Gan et al. 2009; Cabral et al. 2011; Singh et al. 2014; Williams et al. 2014; Lim et al. 2016). Furthermore, several genes within the gene cluster responsible for CsA biosynthesis in Tolypocladium inflatum, including an hCypA homologue, are upregulated in response to insect hemolymph, which is consistent with a role in fungal pathogenesis (Bushley et al. 2013).
Many studies indicate a direct role of cyclophilins in bacterial pathogenesis, since diverse bacteria display reduced infectivity or survival in the host in the absence of a cyclophilin (Delpino et al. 2009; Reffuveille et al. 2012). Yersinia pseudotuberculosis lacking the periplasmic cyclophilin ppiA, along with other PPIase genes, is attenuated in mice infections (Obi et al. 2011). Deletion of both Brucella abortus cyclophilins resulted in a mutant that displayed reduced virulence in mice and defective survival within HeLa cells (Roset et al. 2013). Streptococcus pneumoniae SlrA cyclophilin contributes to the pneumococcal virulence in the first stage of infection (Hermans et al. 2006), and the homologous lipoprotein PpiA suppresses the phagocytosis of S. gordonii and S. mutans by macrophages, playing an important role in the evasion of the host immune response (Mukouhara et al. 2011; Cho et al. 2013). M. tuberculosis cyclophilins are immunogenic proteins that enhance persistence within the host by subverting its stress response (Pandey et al. 2017). An intracellular cyclophilin is required for folding and activity of the Staphylococcus aureus secreted nuclease, which is transported across the cell membrane, along with other virulence factors, by the Sec secretion system in a denatured state (Wiemels et al. 2016).
There is growing evidence that the fungal cyclophilins, particularly the human CypA homologues, are involved in the infection of both animal and plant hosts (Wang et al. 2001; Viaud et al. 2002; Shenton et al. 2012; Singh et al. 2017). In Cryphonectria parasitica, deletion of cyp1 resulted in reduced virulence when the fungus was inoculated in chestnut stems (Chen et al. 2011). A hypovirus mediated cyp1 downregulation possibly contributes to the hypovirulence of C. parasitica following a hypovirus infection (Wang et al. 2016). The BCP1 cyclophilin deletion mutant of Botrytis cinerea causes altered symptoms in bean and tomato leaves (Viaud et al. 2003). Transient silencing of the CYC1 cyclophilin gene in Puccinia triticina compromised growth and sporulation resulting in disease suppression in wheat (Panwar et al. 2013). Deletion of either of two particular cyclophilin genes as well as simultaneous deletion of all eleven cyclophilin genes in Beauveria bassiana resulted in decreased virulence in insect bioassays (Zhou et al. 2016). In addition, the CypB of B. bassiana is involved in its asexual development, dimorphic transition, stress tolerance, and virulence (Chu et al. 2017).
Many fungal cyclophilins are major allergens (Pellon et al. 2014; Buldain et al. 2016), and some cyclophilins of Apicomplexa parasites can modulate the immune response of their intermediate host via sophisticated mechanisms promoting their transmission. Toxoplasma gondii TgCyp18 acts like a chemokine mimic (Aliberti et al. 2003; Yarovinsky et al. 2004), and it regulates the proliferation and migration of host cells (Ibrahim et al. 2010, 2014). In addition, it can inhibit the infectivity of human immunodeficiency viruses by co-receptor antagonism (Golding et al. 2003). The CypA homologue of Schistosoma japonicum is immunomodulatory as well (Han et al. 2012; Li et al. 2013), and a secreted cyclophilin from T. cruzi neutralizes its vector’s antimicrobial peptide trialysin promoting its own survival (Kulkarni et al. 2013).
Conclusions and future directions
Overall, it has now become evident that microbial cyclophilins are involved in diverse biological processes ranging from cellular signal transduction to virulence (Fig. 1). However, until we identify the protein substrates of these enzymes and understand their mechanism of action, we cannot fully appreciate their possible biological functions or their potential use as therapeutic targets. More studies are also required in order to understand whether the presence of multiple prolyl isomerases in most microbes provides a functional redundancy among them. In vivo analysis of additional mutant microbes, structural characterization of more cyclophilins with diverse sizes and localization patterns, and characterization of cyclophilins protein interactome are some of the areas that deserve further attention in future studies in order to better understand how alterations in protein conformation mediated by cyclophilins affect cell biology under physiological and stress conditions.
References
Adams B, Musiyenko A, Kumar R, Barik S (2005) A novel class of dual-family immunophilins. J Biol Chem 280:24308–24314
Aliberti J, Valenzuela JG, Carruthers VB, Hieny S, Andersen J, Charest H, Reis e Sousa C, Fairlamb A, Ribeiro JM, Sher A (2003) Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells. Nat Immunol 4:485–490
Ansari H, Greco G, Luban J (2002) Cyclophilin A peptidyl-prolyl isomerase activity promotes ZPR1 nuclear export. Mol Cell Biol 22:6993–7003
Arévalo-Rodríguez M, Heitman J (2005) Cyclophilin A is localized to the nucleus and controls meiosis in Saccharomyces cerevisiae. Eukaryot Cell 4:17–29
Arévalo-Rodríguez M, Cardenas ME, Wu X, Hanes SD, Heitman J (2000) Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase. EMBO J 19:3739–3749
Barik S (2017) On the role, ecology, phylogeny, and structure of dual-family immunophilins. Cell Stress Chaperones. doi:10.1007/s12192-017-0813-x
Bell A, Monaghan P, Page AP (2006) Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action. Int J Parasitol 36:261–276
Bhaduri A, Misra R, Maji A, Bhetaria PJ, Mishra S, Arora G, Singh LK, Dhasmana N, Dubey N, Virdi JS, Singh Y (2014) Mycobacterium tuberculosis cyclophilin A uses novel signal sequence for secretion and mimics eukaryotic cyclophilins for interaction with host protein repertoire. PLoS One 9:e88090
Blair LJ, Baker JD, Sabbagh JJ, Dickey CA (2015) The emerging role of peptidyl-prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer’s disease. J Neurochem 133:1–13
Breuder T, Hemenway CS, Movva NR, Cardenas ME, Heitman J (1994) Calcineurin is essential in cyclosporin A- and FK506-sensitive yeast strains. Proc Natl Acad Sci USA 91:5372–5376
Brown CR, Cui DY, Hung GG, Chiang HL (2001) Cyclophilin A mediates Vid22p function in the import of fructose-1,6-bisphosphatase into Vid vesicles. J Biol Chem 276:48017–48026
Brust D, Daum B, Breunig C, Hamann A, Kühlbrandt W, Osiewacz HD (2010) Cyclophilin D links programmed cell death and organismal aging in Podospora anserina. Aging Cell 9:761–775
Bukrinsky M (2015) Extracellular cyclophilins in health and disease. Biochim Biophys Acta 1850:2087–2095
Buldain I, Ramirez-Garcia A, Pellon A, Antoran A, Sevilla MJ, Rementeria A, Hernando FL (2016) Cyclophilin and enolase are the most prevalent conidial antigens of Lomentospora prolificans recognized by healthy human salivary IgA and cross-react with Aspergillus fumigatus. Proteomics Clin Appl 10:1058–1067
Bushley KE, Raja R, Jaiswal P, Cumbie JS, Nonogaki M, Boyd AE, Owensby CA, Knaus BJ, Elser J, Miller D, Di Y, McPhail KL, Spatafora JW (2013) The genome of Tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster. PLoS Genet 9:e1003496
Bustos PL, Volta BJ, Perrone AE, Milduberger N, Bua J (2017) A homolog of cyclophilin D is expressed in Trypanosoma cruzi and is involved in the oxidative stress-damage response. Cell Death Discov 3:16092
Cabral A, Stassen JH, Seidl MF, Bautor J, Parker JE, Van den Ackerveken G (2011) Identification of Hyaloperonospora arabidopsidis transcript sequences expressed during infection reveals isolate-specific effectors. PLoS ONE 6:e19328
Chakraborty A, Sen B, Datta R, Datta AK (2004) Isomerase-independent chaperone function of cyclophilin ensures aggregation prevention of adenosine kinase both in vitro and under in vivo conditions. BioChemistry 43:11862–11872
Chen MM, Jiang M, Shang J, Lan X, Yang F, Huang J, Nuss DL, Chen B (2011) CYP1, a hypovirus-regulated cyclophilin, is required for virulence in the chestnut blight fungus. Mol Plant Pathol 12:239–246
Cho K, Arimoto T, Igarashi T, Yamamoto M (2013) Involvement of lipoprotein PpiA of Streptococcus gordonii in evasion of phagocytosis by macrophages. Mol Oral Microbiol 28:379–391
Christoforides E, Dimou M, Katinakis P, Bethanis K, Karpusas M (2012) Structure of a bacterial cytoplasmic cyclophilin A in complex with a tetrapeptide. Acta Crystallogr Sect F 68:259–264
Chu ZJ, Sun HH, Ying SH, Feng MG (2017) Vital role for cyclophilin B (CypB) in asexual development, dimorphic transition and virulence of Beauveria bassiana. Fungal Genet Biol 105:8–15
Clubb RT, Ferguson SB, Walsh CT, Wagner G (1994) Three-dimensional solution structure of Escherichia coli periplasmic cyclophilin. BioChemistry 33:2761–2772
Compton LA, Davis JM, Macdonald JR, Bächinger HP (1992) Structural and functional characterization of Escherichia coli peptidyl-prolyl cis-trans isomerases. Eur J Biochem 206:927–934
Davis TL, Walker JR, Campagna-Slater V, Finerty PJ, Paramanathan R, Bernstein G, MacKenzie F, Tempel W, Ouyang H, Lee WH, Eisenmesser EZ, Dhe-Paganon S (2010) Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases. PLoS Biol 8:e1000439
Delpino MV, Comerci DJ, Wagner MA, Eschenbrenner M, Mujer CV, Ugalde RA, Fossati CA, Baldi PC, Delvecchio VG (2009) Differential composition of culture supernatants from wild-type Brucella abortus and its isogenic virB mutants. Arch Microbiol 191:571–581
Dimou M, Venieraki A, Liakopoulos G, Kouri ED, Tampakaki A, Katinakis P (2011) Gene expression and biochemical characterization of Azotobacter vinelandii cyclophilins and Protein Interaction Studies of the cytoplasmic isoform with dnaK and lpxH. J Mol Microbiol Biotechnol 20:176–190
Dimou M, Venieraki A, Zografou C, Katinakis P (2012a) The cytoplasmic cyclophilin from Azotobacter vinelandii interacts with phosphate acetyltransferase isoforms enhancing their in vitro activity. Mol Biol Rep 39:4135–4143
Dimou M, Zografou C, Venieraki A, Katinakis P (2012b) Functional interaction of Azotobacter vinelandii cytoplasmic cyclophilin with the biotin carboxylase subunit of acetyl-CoA carboxylase. Biochem Biophys Res Commun 424:736–739
Dolinski K, Muir S, Cardenas M, Heitman J (1997) All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 94:13093–13098
Doshi U, McGowan LC, Ladani ST, Hamelberg D (2012) Resolving the complex role of enzyme conformational dynamics in catalytic function. Proc Natl Acad Sci USA 109:5699–5704
Droll D, Archer S, Fenn K, Delhi P, Matthews K, Clayton C (2010) The trypanosome Pumilio-domain protein PUF7 associates with a nuclear cyclophilin and is involved in ribosomal RNA maturation. FEBS Lett 584:1156–1162
Duina AA, Chang HC, Marsh JA, Lindquist S, Gaber RF (1996) A cyclophilin function in Hsp90-dependent signal transduction. Science 274:1713–1715
Edwards KJ, Ollis DL, Dixon NE (1997) Crystal structure of cytoplasmic Escherichia coli peptidyl-prolyl isomerase: evidence for decreased mobility of loops upon complexation. J Mol Biol 271:258–265
Eisenmesser EZ, Millet O, Labeikovsky W, Korzhnev DM, Wolf-Watz M, Bosco DA, Skalicky JJ, Kay LE, Kern D (2005) Intrinsic dynamics of an enzyme underlies catalysis. Nature 438:117–121
Faou P, Tropschug M (2003) A novel binding protein for a member of CyP40-type Cyclophilins: N. crassa CyPBP37, a growth and thiamine regulated protein homolog to yeast Thi4p. J Mol Biol 333:831–844
Fischer G, Wittmann-Liebold B, Lang K, Kiefhaber T, Schmid FX (1989) Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337:476–478
Foor F, Parent SA, Morin N, Dahl AM, Ramadan N, Chrebet G, Bostian KA, Nielsen JB (1992) Calcineurin mediates inhibition by FK506 and cyclosporin of recovery from alpha-factor arrest in yeast. Nature 360:682–684
Gan PH, Shan W, Blackman LM, Hardham AR (2009) Characterization of cyclophilin-encoding genes in Phytophthora. Mol Genet Genom 281:565–578
Geisler M, Bailly A, Ivanchenko M (2016) Master and servant: Regulation of auxin transporters by FKBPs and cyclophilins. Plant Sci 245:1–10
Golding H, Aliberti J, King LR, Manischewitz J, Andersen J, Valenzuela J, Landau NR, Sher A (2003) Inhibition of HIV-1 infection by a CCR5-binding cyclophilin from Toxoplasma gondii. Blood 102:3280–3286
Göthel SF, Herrler M, Marahiel MA (1996) Peptidyl-prolyl cis-trans isomerase of Bacillus subtilis: identification of residues involved in cyclosporin A affinity and catalytic efficiency. BioChemistry 35:3636–3640
Graumann P, Schröder K, Schmid R, Marahiel MA (1996) Cold shock stress-induced proteins in Bacillus subtilis. J Bacteriol 178:4611–4619
Gutiérrez-Aguilar M, Baines CP (2015) Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta 1850:2041–2047
Han H, Peng J, Hong Y, Fu Z, Xu J, Lin J, Tao J (2012) Molecular cloning and characterization of a cyclophilin A homologue from Schistosoma japonicum. Parasitol Res 111:807–817
Hassidim M, Schwarz R, Lieman-Hurwitz J, Marco E, Ronen-Tarazi M, Kaplan A (1992) A cyanobacterial gene encoding peptidyl-prolyl cis-trans Isomerase. Plant Physiol 100:1982–1986
Hayano T, Takahashi N, Kato S, Maki N, Suzuki M (1991) Two distinct forms of peptidylprolyl-cis-trans-isomerase are expressed separately in periplasmic and cytoplasmic compartments of Escherichia coli cells. BioChemistry 30:3041–3048
Henriksson LM, Johansson P, Unge T, Mowbray SL (2004) X-ray structure of peptidyl-prolyl cis-trans isomerase A from Mycobacterium tuberculosis. Eur J Biochem 271:4107–4113
Hermans PW, Adrian PV, Albert C, Estevão S, Hoogenboezem T, Luijendijk IH, Kamphausen T, Hammerschmidt S (2006) The streptococcal lipoprotein rotamase A (SlrA) is a functional peptidyl-prolyl isomerase involved in pneumococcal colonization. J Biol Chem 281:968–976
Herrler M, Bang H, Marahiel MA (1994) Cloning and characterization of ppiB, a Bacillus subtilis gene which encodes a cyclosporin A-sensitive peptidyl-prolyl cis-trans isomerase. Mol Microbiol 11:1073–1083
Holliday MJ, Camilloni C, Armstrong GS, Isern NG, Zhang F, Vendruscolo M, Eisenmesser EZ (2015) Structure and dynamics of GeoCyp: a thermophilic cyclophilin with a novel substrate binding mechanism that functions efficiently at low temperatures. BioChemistry 54:3207–3217
Hopkins S, Gallay PA (2015) The role of immunophilins in viral infection. Biochim Biophys Acta 1850:2103–2110
Ibrahim HM, Xuan X, Nishikawa Y (2010) Toxoplasma gondii cyclophilin 18 regulates the proliferation and migration of murine macrophages and spleen cells. Clin Vaccine Immunol 17:1322–1329
Ibrahim HM, Nishimura M, Tanaka S, Awadin W, Furuoka H, Xuan X, Nishikawa Y (2014) Overproduction of Toxoplasma gondii cyclophilin-18 regulates host cell migration and enhances parasite dissemination in a CCR5-independent manner. BMC Microbiol 14:76
Iida T, Furutani M, Iwabuchi T, Maruyama T (1997) Gene for a cyclophilin-type peptidyl-prolyl cis-trans isomerase from a halophilic archaeum, Halobacterium cutirubrum. Gene 204:139–144
Jakob RP, Schmidpeter PA, Koch JR, Schmid FX, Maier T (2016) Structural and functional characterization of a novel family of cyclophilins, the AquaCyps. PLoS ONE 11:e0157070
Joseph JD, Heitman J, Means AR (1999) Molecular cloning and characterization of Aspergillus nidulans cyclophilin B. Fungal Genet Biol 27:55–66
Kim IS, Kim HY, Shin SY, Kim YS, Lee DH, Park KM, Yoon HS (2010a) A cyclophilin A CPR1 overexpression enhances stress acquisition in Saccharomyces cerevisiae. Mol Cells 29:567–574
Kim IS, Shin SY, Kim YS, Kim HY, Lee DH, Park KM, Yoon HS, Jin I (2010b) Expression of yeast cyclophilin A (Cpr1) provides improved stress tolerance in Escherichia coli. J Microbiol Biotechnol 20:974–977
Kim IS, Jin I, Yoon HS (2011) Decarbonylated cyclophilin A Cpr1 protein protects Saccharomyces cerevisiae KNU5377Y when exposed to stress induced by menadione. Cell Stress Chaperones 16:1–14
Kim EY, Choi YH, Choi CG, Nam TJ (2017) Effects of the cyclophilin-type peptidylprolyl cis-trans isomerase from Pyropia yezoensis against hydrogen peroxide-induced oxidative stress in HepG2 cells. Mol Med Rep 15:4132–4138
Kleerebezem M, Heutink M, Tommassen J (1995) Characterization of an Escherichia coli rotA mutant, affected in periplasmic peptidyl-prolyl cis/trans isomerase. Mol Microbiol 18:313–320
Kok RG, Christoffels VM, Vosman B, Hellingwerf KJ (1994) A gene of Acinetobacter calcoaceticus BD413 encodes a periplasmic peptidyl-prolyl cis-trans isomerase of the cyclophilin sub-class that is not essential for growth. Biochim Biophys Acta 1219:601–606
Kramer P, Jung AT, Hamann A, Osiewacz HD Cyclophilin D (2016) Is involved in the regulation of autophagy and affects the lifespan of P. anserina in response to mitochondrial oxidative stress. Front Genet 7:165
Krücken J, Greif G, von Samson-Himmelstjerna G (2009) In silico analysis of the cyclophilin repertoire of apicomplexan parasites. Parasites Vectors 2:27
Kulkarni MM, Karafova A, Kamysz W, Schenkman S, Pelle R, McGwire BS (2013) Secreted trypanosome cyclophilin inactivates lytic insect defense peptides and induces parasite calcineurin activation and infectivity. J Biol Chem 288:8772–8784
Kumar N, Gaur D, Gupta A, Puri A, Sharma D (2015) Hsp90-associated immunophilin homolog Cpr7 is required for the mitotic stability of [URE3] prion in Saccharomyces cerevisiae. PLoS Genet 11:e1005567
Ladani ST, Souffrant MG, Barman A, Hamelberg D (2015) Computational perspective and evaluation of plausible catalytic mechanisms of peptidyl-prolyl cis-trans isomerases. Biochim Biophys Acta 1850:1994–2004
Leneghan D, Bell A (2015) Immunophilin-protein interactions in Plasmodium falciparum. Parasitology 142:1404–1414
Li J, Zhuang W, Cong L, Shi W, Cai X, Huang F, Liao Y, Liu Y, Li J, Chen C, Chen XP (2013) Cyclophilin A from Schistosoma japonicum promotes a Th2 response in mice. Parasites Vectors 6:330
Lim F-H, Fakhrana IN, Rasid OA, Idris AS, Ho C-L, Shaharuddin NA, Parveez GKA (2016) Molecular cloning and expression analysis of Ganoderma boninense cyclophilins at different growth and infection stages. Physiol Mol Plant Pathol. doi:10.1016/j.pmpp.2016.05.005
Limacher A, Kloer DP, Flückiger S, Folkers G, Crameri R, Scapozza L (2006) The crystal structure of Aspergillus fumigatus cyclophilin reveals 3D domain swapping of a central element. Structure 14:185–195
Lin JY, Mendu V, Pogany J, Qin J, Nagy PD (2012) The TPR domain in the host Cyp40-like cyclophilin binds to the viral replication protein and inhibits the assembly of the tombusviral replicase. PLoS Pathog 8:e1002491
Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL (1991a) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–815
Liu J, Chen CM, Walsh CT (1991b) Human and Escherichia coli cyclophilins: sensitivity to inhibition by the immunosuppressant cyclosporin A correlates with a specific tryptophan residue. BioChemistry 30:2306–2310
Manteca A, Pelaez AI, Zardoya R, Sanchez J (2006) Actinobacteria cyclophilins: phylogenetic relationships and description of new class- and order-specific paralogues. J Mol Evol 63:719–732
Matouschek A, Rospert S, Schmid K, Glick BS, Schatz G (1995) Cyclophilin catalyzes protein folding in yeast mitochondria. Proc Natl Acad Sci U S A 92:6319–6323
Molshanski-Mor S, Yosef I, Kiro R, Edgar R, Manor M, Gershovits M, Laserson M, Pupko T, Qimron U (2014) Revealing bacterial targets of growth inhibitors encoded by bacteriophage T7. Proc Natl Acad Sci USA 111:18715–18720
Mukherjee D, Patra H, Laskar A, Dasgupta A, Maiti NC, Datta AK (2013) Cyclophilin-mediated reactivation pathway of inactive adenosine kinase aggregates. Arch Biochem Biophys 537:82–90
Mukouhara T, Arimoto T, Cho K, Yamamoto M, Igarashi T (2011) Surface lipoprotein PpiA of Streptococcus mutans suppresses scavenger receptor MARCO-dependent phagocytosis by macrophages. Infect Immun 79:4933–4940
Nagashima K, Mitsuhashi S, Kamino K, Maruyama T (1994) Cyclosporin A sensitive peptidyl-prolyl cis-trans isomerase in a halophilic archaeum, Halobacterium cutirubrum. Biochem Biophys Res Commun 198:466–472
Nigro P, Pompilio G, Capogrossi MC (2013) Cyclophilin A: a key player for human disease. Cell Death Dis 4:e888
Obi IR, Nordfelth R, Francis MS (2011) Varying dependency of periplasmic peptidylprolyl cis-trans isomerases in promoting Yersinia pseudotuberculosis stress tolerance and pathogenicity. Biochem J 439:321–332
Ohi MD, Link AJ, Ren L, Jennings JL, McDonald WH, Gould KL (2002) Proteomics analysis reveals stable multiprotein complexes in both fission and budding yeasts containing Myb-related Cdc5p/Cef1p, novel pre-mRNA splicing factors, and snRNAs. Mol Cell Biol 22:2011–2024
Pahl A, Uhlein M, Bang H, Schlumbohm W, Keller U (1992) Streptomycetes possess peptidyl-prolyl cis-trans isomerases that strongly resemble cyclophilins from eukaryotic organisms. Mol Microbiol 6:3551–3558
Pandey S, Sharma A, Tripathi D, Kumar A, Khubaib M, Bhuwan M, Chaudhuri TK, Hasnain SE, Ehtesham NZ (2016) Mycobacterium tuberculosis peptidyl-prolyl isomerases also exhibit chaperone like activity in-vitro and in-vivo. PLoS ONE 11:e0150288
Pandey S, Tripathi D, Khubaib M, Kumar A, Sheikh JA, Sumanlatha G, Ehtesham NZ, Hasnain SE (2017) Mycobacterium tuberculosis peptidyl-prolyl isomerases are immunogenic, alter cytokine profile and aid in intracellular survival. Front Cell Infect Microbiol 7:38
Panwar V, McCallum B, Bakkeren G (2013) Host-induced gene silencing of wheat leaf rust fungus Puccinia triticina pathogenicity genes mediated by the Barley stripe mosaic virus. Plant Mol Biol 81:595–608
Pellon A, Ramirez-Garcia A, Antoran A, Fernandez-Molina JV, Abad-Diaz-de-Cerio A, Montañez D, Sevilla MJ, Rementeria A, Hernando FL (2014) Scedosporium prolificans immunomes against human salivary immunoglobulin A. Fungal Biol 118:94–105
Pemberton TJ (2006) Identification and comparative analysis of sixteen fungal peptidyl-prolyl cis/trans isomerase repertoires. BMC Genom 7:244
Pissavin C, Hugouvieux-Cotte-Pattat N (1997) Characterization of a periplasmic peptidyl-prolyl cis-trans isomerase in Erwinia chrysanthemi. FEMS Microbiol Lett 157:59–65
Ponmani T, Guo R, Ki JS (2015) A novel cyclophilin gene from the dinoflagellate Prorocentrum minimum and its possible role in the environmental stress response. Chemosphere 139:260–267
Ratajczak T (2015) Steroid receptor-associated immunophilins: candidates for diverse drug-targeting approaches in disease. Curr Mol Pharmacol 9:66–95
Reffuveille F, Connil N, Sanguinetti M, Posteraro B, Chevalier S, Auffray Y, Rince A (2012) Involvement of peptidylprolyl cis/trans isomerases in Enterococcus faecalis virulence. Infect Immun 80:1728–1735
Rêgo JV, Duarte AP, Liarte DB, de Carvalho Sousa F, Barreto HM, Bua J, Romanha AJ, Rádis-Baptista G, Murta SM (2015) Molecular characterization of Cyclophilin (TcCyP19) in Trypanosoma cruzi populations susceptible and resistant to benznidazole. Exp Parasitol 148:73–80
Roset MS, García Fernández L, DelVecchio VG, Briones G (2013) Intracellularly induced cyclophilins play an important role in stress adaptation and virulence of Brucella abortus. Infect Immun 81:521–530
Schiene C, Fischer G (2000) Enzymes that catalyse the restructuring of proteins. Curr Opin Struct Biol 10:40–45
Schiene-Fischer C, Aumüller T, Fischer G (2013) Peptide bond cis/trans isomerases: a biocatalysis perspective of conformational dynamics in proteins. Top Curr Chem 328:35–67
Schmidt B, Tradler T, Rahfeld JU, Ludwig B, Jain B, Mann K, Rücknagel KP, Janowski B, Schierhorn A, Küllertz G, Hacker J, Fischer G (1996) A cyclophilin-like peptidyl-prolyl cis/trans isomerase from Legionella pneumophila–characterization, molecular cloning and overexpression. Mol Microbiol 21:1147–1160
Shenton MR, Berberich T, Kamo M, Yamashita T, Taira H, Terauchi R (2012) Use of intercellular washing fluid to investigate the secreted proteome of the rice-Magnaporthe interaction. J Plant Res 125:311–316
Singh S, Dubey VK (2016) Quantitative proteome analysis of Leishmania donovani under spermidine starvation. PLoS ONE 11:e0154262
Singh K, Zouhar M, Mazakova J, Rysanek P (2014) Genome wide identification of the immunophilin gene family in Leptosphaeria maculans: a causal agent of Blackleg disease in Oilseed Rape (Brassica napus). OMICS 18:645–657
Singh K, Winter M, Zouhar M, Rysanek P (2017) Cyclophilins: less studied proteins with critical roles in pathogenesis. Phytopathology. doi:10.1094/PHYTO-05-17-0167-RVW
Skagia A, Zografou C, Vezyri E, Venieraki A, Katinakis P, Dimou M (2016) Cyclophilin PpiB is involved in motility and biofilm formation via its functional association with certain proteins. Genes Cells 21:833–851
Skagia A, Vezyri E, Sigala M, Kokkinou A, Karpusas M, Venieraki A, Katinakis P, Dimou M (2017a) Structural and functional analysis of cyclophilin PpiB mutants supports an in vivo function not limited to prolyl isomerization activity. Genes Cells 22:32–44
Skagia A, Zografou C, Venieraki A, Fasseas C, Katinakis P, Dimou M (2017b) Functional analysis of the cyclophilin PpiB role in bacterial cell division. Genes Cells. doi:10.1111/gtc.12514
Skruzný M, Ambrozková M, Fuková I, Martínková K, Blahůsková A, Hamplová L, Půta F, Folk P (2001) Cyclophilins of a novel subfamily interact with SNW/SKIP coregulator in Dictyostelium discoideum and Schizosaccharomyces pombe. Biochim Biophys Acta 1521:146–151
Söderberg MA, Cianciotto NP A (2008) Legionella pneumophila peptidyl-prolyl cis-trans isomerase present in culture supernatants is necessary for optimal growth at low temperatures. Appl Environ Microbiol 74:1634–1638
Sykes K, Gething MJ, Sambrook J (1993) Proline isomerases function during heat shock. Proc Natl Acad Sci USA 90:5853–5857
Takahashi N, Hayano T, Suzuki M (1989) Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 337:473–475
Tenge VR, Zuehlke AD, Shrestha N, Johnson JL (2015) The Hsp90 cochaperones Cpr6, Cpr7, and Cns1 interact with the intact ribosome. Eukaryot Cell 14:55–63
Tesic M, Marsh JA, Cullinan SB, Gaber RF (2003) Functional interactions between Hsp90 and the co-chaperones Cns1 and Cpr7 in Saccharomyces cerevisiae. J Biol Chem 278:32692–32701
Thai V, Renesto P, Fowler CA, Brown DJ, Davis T, Gu W, Pollock DD, Kern D, Raoult D, Eisenmesser EZ (2008) Structural, biochemical, and in vivo characterization of the first virally encoded cyclophilin from the Mimivirus. J Mol Biol 378:71–86
Thomloudi EE, Skagia A, Venieraki A, Katinakis P, Dimou M (2017) Functional analysis of the two cyclophilin isoforms of Sinorhizobium meliloti. World J Microbiol Biotechnol 33:28
Trémillon N, Morello E, Llull D, Mazmouz R, Gratadoux JJ, Guillot A, Chapot-Chartier MP, Monlezun L, Solé V, Ginisty H, Poquet I (2012) PpiA, a surface PPIase of the cyclophilin family in Lactococcus lactis. PLoS ONE 7:e33516
Trivedi DK, Ansari MW, Dutta T, Singh P, Tuteja N (2013a) Molecular characterization of cyclophilin A-like protein from Piriformospora indica for its potential role to abiotic stress tolerance in E. coli. BMC Res Notes 6:555
Trivedi DK, Bhatt H, Pal RK, Tuteja R, Garg B, Johri AK, Bhavesh NS, Tuteja N (2013b) Structure of RNA-interacting cyclophilin A-like protein from Piriformospora indica that provides salinity-stress tolerance in plants. Sci Rep 3:3001
Tropschug M, Barthelmess IB, Neupert W (1989) Sensitivity to cyclosporin A is mediated by cyclophilin in Neurospora crassa and Saccharomyces cerevisiae. Nature 342:953–955
Ulrich A, Wahl MC (2014) Structure and evolution of the spliceosomal peptidyl-prolyl cis-trans isomerase Cwc27. Acta Crystallogr D 70:3110–3123
Ünal CM, Steinert M (2014) Microbial peptidyl-prolyl cis/trans isomerases (PPIases): virulence factors and potential alternative drug targets. Microbiol Mol Biol Rev 78:544–571
Vasudevan D, Gopalan G, Kumar A, Garcia VJ, Luan S, Swaminathan K (2015) Plant immunophilins: a review of their structure-function relationship. Biochim Biophys Acta 1850:2145–2158
Viaud MC, Balhadère PV, Talbot NJ (2002) A Magnaporthe grisea cyclophilin acts as a virulence determinant during plant infection. Plant Cell 14:917–930
Viaud M, Brunet-Simon A, Brygoo Y, Pradier JM, Levis C (2003) Cyclophilin A and calcineurin functions investigated by gene inactivation, cyclosporin A inhibition and cDNA arrays approaches in the phytopathogenic fungus Botrytis cinerea. Mol Microbiol 50:1451–1465
Wang P, Heitman J (2005) The cyclophilins. Genome Biol 6:226
Wang P, Cardenas ME, Cox GM, Perfect JR, Heitman J (2001) Two cyclophilin A homologs with shared and distinct functions important for growth and virulence of Cryptococcus neoformans. EMBO Rep 2:511–518
Wang J, Shi L, He X, Lu L, Li X, Chen B (2016) Comparative secretome analysis reveals perturbation of host secretion pathways by a hypovirus. Sci Rep 6:34308
Wiemels RE, Cech SM, Meyer NM, Burke CA, Weiss A, Parks AR, Shaw LN, Carroll RK (2016) An intracellular peptidyl-prolyl cis/trans isomerase is required for folding and activity of the Staphylococcus aureus secreted virulence factor nuclease. J Bacteriol. doi:10.1128/JB.00453-16
Williams HL, Sturrock RN, Islam MA, Hammett C, Ekramoddoullah AK, Leal I (2014) Gene expression profiling of candidate virulence factors in the laminated root rot pathogen Phellinus sulphurascens. BMC Genom 15:603
Yarovinsky F, Andersen JF, King LR, Caspar P, Aliberti J, Golding H, Sher A (2004) Structural determinants of the anti-HIV activity of a CCR5 antagonist derived from Toxoplasma gondii. J Biol Chem 279:53635–53642
Yau WL, Blisnick T, Taly JF, Helmer-Citterich M, Schiene-Fischer C, Leclercq O, Li J, Schmidt-Arras D, Morales MA, Notredame C, Romo D, Bastin P, Späth GF (2010) Cyclosporin A treatment of Leishmania donovani reveals stage-specific functions of cyclophilins in parasite proliferation and viability. PLoS Negl Trop Dis 4:e729
Yau WL, Pescher P, MacDonald A, Hem S, Zander D, Retzlaff S, Blisnick T, Rotureau B, Rosenqvist H, Wiese M, Bastin P, Clos J, Späth GF (2014) The Leishmania donovani chaperone cyclophilin 40 is essential for intracellular infection independent of its stage-specific phosphorylation status. Mol Microbiol 93:80–97
Yau WL, Lambertz U, Colineau L, Pescher P, MacDonald A, Zander D, Retzlaff S, Eick J, Reiner NE, Clos J, Späth GF (2016) Phenotypic Characterization of a Leishmania donovani Cyclophilin 40 Null Mutant. J Eukaryot Microbiol 63:823–833
Zhang XC, Wang WD, Wang JS, Pan JC (2013) PPIase independent chaperone-like function of recombinant human Cyclophilin A during arginine kinase refolding. FEBS Lett 587:666–672
Zhou Y, Keyhani NO, Zhang Y, Luo Z, Fan Y, Li Y, Zhou Q, Chen J, Pei Y (2016) Dissection of the contributions of cyclophilin genes to development and virulence in a fungal insect pathogen. Environ Microbiol 18:3812–3826
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Dimou, M., Venieraki, A. & Katinakis, P. Microbial cyclophilins: specialized functions in virulence and beyond. World J Microbiol Biotechnol 33, 164 (2017). https://doi.org/10.1007/s11274-017-2330-6
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DOI: https://doi.org/10.1007/s11274-017-2330-6