Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Microbial cyclophilins: specialized functions in virulence and beyond


Cyclophilins belong to the superfamily of peptidyl-prolyl cis/trans isomerases (PPIases, EC:, 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.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. Adams B, Musiyenko A, Kumar R, Barik S (2005) A novel class of dual-family immunophilins. J Biol Chem 280:24308–24314

  2. 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

  3. Ansari H, Greco G, Luban J (2002) Cyclophilin A peptidyl-prolyl isomerase activity promotes ZPR1 nuclear export. Mol Cell Biol 22:6993–7003

  4. Arévalo-Rodríguez M, Heitman J (2005) Cyclophilin A is localized to the nucleus and controls meiosis in Saccharomyces cerevisiae. Eukaryot Cell 4:17–29

  5. 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

  6. Barik S (2017) On the role, ecology, phylogeny, and structure of dual-family immunophilins. Cell Stress Chaperones. doi:10.1007/s12192-017-0813-x

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Bukrinsky M (2015) Extracellular cyclophilins in health and disease. Biochim Biophys Acta 1850:2087–2095

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. Clubb RT, Ferguson SB, Walsh CT, Wagner G (1994) Three-dimensional solution structure of Escherichia coli periplasmic cyclophilin. BioChemistry 33:2761–2772

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. Duina AA, Chang HC, Marsh JA, Lindquist S, Gaber RF (1996) A cyclophilin function in Hsp90-dependent signal transduction. Science 274:1713–1715

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. Gan PH, Shan W, Blackman LM, Hardham AR (2009) Characterization of cyclophilin-encoding genes in Phytophthora. Mol Genet Genom 281:565–578

  40. Geisler M, Bailly A, Ivanchenko M (2016) Master and servant: Regulation of auxin transporters by FKBPs and cyclophilins. Plant Sci 245:1–10

  41. 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

  42. 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

  43. Graumann P, Schröder K, Schmid R, Marahiel MA (1996) Cold shock stress-induced proteins in Bacillus subtilis. J Bacteriol 178:4611–4619

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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

  50. 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

  51. 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

  52. Hopkins S, Gallay PA (2015) The role of immunophilins in viral infection. Biochim Biophys Acta 1850:2103–2110

  53. 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

  54. 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

  55. 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

  56. 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

  57. Joseph JD, Heitman J, Means AR (1999) Molecular cloning and characterization of Aspergillus nidulans cyclophilin B. Fungal Genet Biol 27:55–66

  58. 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

  59. 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

  60. 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

  61. 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

  62. 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

  63. 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

  64. 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

  65. Krücken J, Greif G, von Samson-Himmelstjerna G (2009) In silico analysis of the cyclophilin repertoire of apicomplexan parasites. Parasites Vectors 2:27

  66. 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

  67. 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

  68. 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

  69. Leneghan D, Bell A (2015) Immunophilin-protein interactions in Plasmodium falciparum. Parasitology 142:1404–1414

  70. 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

  71. 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

  72. 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

  73. 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

  74. 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

  75. 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

  76. 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

  77. 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

  78. 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

  79. 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

  80. 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

  81. 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

  82. Nigro P, Pompilio G, Capogrossi MC (2013) Cyclophilin A: a key player for human disease. Cell Death Dis 4:e888

  83. 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

  84. 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

  85. 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

  86. 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

  87. 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

  88. 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

  89. 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

  90. Pemberton TJ (2006) Identification and comparative analysis of sixteen fungal peptidyl-prolyl cis/trans isomerase repertoires. BMC Genom 7:244

  91. 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

  92. 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

  93. Ratajczak T (2015) Steroid receptor-associated immunophilins: candidates for diverse drug-targeting approaches in disease. Curr Mol Pharmacol 9:66–95

  94. 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

  95. 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

  96. 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

  97. Schiene C, Fischer G (2000) Enzymes that catalyse the restructuring of proteins. Curr Opin Struct Biol 10:40–45

  98. 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

  99. 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

  100. 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

  101. Singh S, Dubey VK (2016) Quantitative proteome analysis of Leishmania donovani under spermidine starvation. PLoS ONE 11:e0154262

  102. 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

  103. 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

  104. 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

  105. 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

  106. 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

  107. 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

  108. 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

  109. Sykes K, Gething MJ, Sambrook J (1993) Proline isomerases function during heat shock. Proc Natl Acad Sci USA 90:5853–5857

  110. Takahashi N, Hayano T, Suzuki M (1989) Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 337:473–475

  111. 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

  112. 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

  113. 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

  114. 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

  115. 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

  116. 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

  117. 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

  118. 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

  119. Ulrich A, Wahl MC (2014) Structure and evolution of the spliceosomal peptidyl-prolyl cis-trans isomerase Cwc27. Acta Crystallogr D 70:3110–3123

  120. 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

  121. 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

  122. Viaud MC, Balhadère PV, Talbot NJ (2002) A Magnaporthe grisea cyclophilin acts as a virulence determinant during plant infection. Plant Cell 14:917–930

  123. 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

  124. Wang P, Heitman J (2005) The cyclophilins. Genome Biol 6:226

  125. 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

  126. 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

  127. 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

  128. 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

  129. 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

  130. 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

  131. 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

  132. 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

  133. 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

  134. 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

Download references


We apologize to the colleagues whose work we could not cite due to space limitations.

Author information

Correspondence to Maria Dimou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation


  • Chaperone
  • Cyclophilin
  • Cyclosporin
  • Function
  • Gene distribution
  • Immunomodulation
  • Pathogenesis
  • Peptidyl-prolyl cis/trans isomerase
  • Stress tolerance
  • Structure
  • Virulence