Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 140 No. 2930 (2010)

Cathepsins and their involvement in immune responses

  • S Conus
DOI
https://doi.org/10.4414/smw.2010.13042
Cite this as:
Swiss Med Wkly. 2010;140:w13042
Published
19.07.2010

Summary

The immune system is composed of an enormous variety of cells and molecules that generate a collective and coordinated response on exposure to foreign antigens, called the immune response. Within the immune response, endo-lysosomal proteases play a key role. In this review we cover specific roles of cathepsins in innate and adaptive immunity, as well as their implication in the pathogenesis of several diseases.

References

  1. Conus S, Simon H-U. Cathepsins: key modulators of cell death and inflammatory responses. Biochem Pharmacol. 2008;76(11):1374–82.
  2. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989;320(6):365–77.
  3. Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000;407(6805):784–8.
  4. Simon H-U. Neutrophil apoptosis pathways and their modifications in inflammation. Immunol Rev. 2003;193(1):101–10.
  5. Lamkanfi M, Festjens N, Declercq W, Berghe TV, Vandenabeele P. Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 2006;14(1):44–55.
  6. Turk B, Turk D, Turk V. Lysosomal cysteine proteases: more than scavengers. Biochem Biophys Acta. 2000;1477(1-2):98–111.
  7. Foghsgaard L, Wissing D, Mauch D, Lademann U, Bastholm L, Boes M, et al. Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor. J Cell Biol. 2001;153(5):999–1010.
  8. Guicciardi ME, Miyoshi H, Bronk SF, Gores GJ. Cathepsin B knockout mice are resistant to tumor necrosis factor-{alpha}-mediated hepatocyte apoptosis and liver injury: implications for therapeutic applications. Am J Pathol. 2001;159(6):2045–54.
  9. Salvesen GS. A lysosomal protease enters the death scene. J Clin Invest. 2001;107(1):21–3.
  10. Roberg K, Kagedal K, Ollinger K. Microinjection of cathepsin D induces caspase-dependent apoptosis in fibroblasts. Am J Pathol. 2002;161(1):89–96.
  11. Turk B, Stoka V, Rozman-Pungercar J, Cirman T, Droga-Mazovec G, Oresic K, et al. Apoptotic pathways: involvement of lysosomal proteases. Biol Chem. 2002;383:1035–44.
  12. Lockshin RA, Zakeri Z. Caspase-independent cell death? Oncogene. 2004;23(16):2766–73.
  13. Friedrichs B, Tepel C, Reinheckel T, Deussing J, von Figura K, Herzog V, et al. Thyroid functions of mouse cathepsins B, K, and L. J Clin Invest. 2003;111(11):1733–45.
  14. Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des. 2007;13:387–403.
  15. Holt OJ, Gallo F, Griffiths GM. Regulating secretory lysosomes. J Biochem. 2006;140(1):7–12.
  16. Dell’Angelica EC, Mullis C, Caplan S, Bonifacino JS. Lysosome-related organelles. FASEB J. 2000;14(10):1265–78.
  17. Blott EJ, Griffiths GM. Secretory lysosomes. Nat Rev Mol Cell Biol. 2002;3(2):122–31.
  18. Turk V, Turk B, Turk D. Lysosomal cysteine proteases: facts and opportunities. EMBO J. 2001;20(17):4629–33.
  19. Rossi A, Deveraux Q, Turk B, Sali A. Comprehensive search for cysteine cathepsins in the human genome. Biol Chem. 2004;385(5):363–72.
  20. Barrett AJ, Rawlings ND, Woessner JF. Handbook of proteolytic enzymes. (New York, USA: Academic Press) 2004.
  21. Zavasnik-Bergant T, Turk B. Cysteine cathepsins in the immune response. Tissue Antigens. 2006;67(5):349–55.
  22. Turk B, Turk D, Salvesen GS. Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators. Curr Pharm Des. 2002;8(18):1623–37.
  23. Chwieralski CE, Welte T, Bühling F. Cathepsin-regulated apoptosis. Apoptosis. 2006;11(2):143–9.
  24. Zavasnik-Bergant T, Turk B. Cysteine proteases: destruction ability versus immunomodulation capacity in immune cells. Biol Chem. 2007;388(11):1141–9.
  25. Guicciardi ME, Deussing J, Miyoshi H, Bronk SF, Svingen PA, Peters C, et al. Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest. 2000;106(9):1127–37.
  26. Stoka V, Turk B, Schendel SL, Kim TH, Cirman T, Snipas SJ, et al. Lysosomal protease pathways to apoptosis. Cleavage of Bid, not pro-caspases, is the most likely route. J Biol Chem. 2001;276(5):3149–57.
  27. Li W, Yuan X, Nordgren G, Dalen H, Dubowchik GM, Firestone RA, et al. Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett. 2000;470(1):35–9.
  28. Boya P, Andreau K, Poncet D, Zamzami N, Perfettini J-L, Metivier D, et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J Exp Med. 2003;197(10):1323–34.
  29. Conus S, Perozzo R, Reinheckel T, Peters C, Scapozza L, Yousefi S, et al. Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation. J Exp Med. 2008;205(3):685–98.
  30. Blomgran R, Zheng L, Stendahl O. Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization. J Leukoc Biol. 2007;81(5):1213–23.
  31. Asagiri M, Hirai T, Kunigami T, Kamano S, Gober H-J, Okamoto K, et al. Cathepsin K-dependent Toll-like receptor 9 signalling revealed in experimental arthritis. Science. 2008;319(5863):624–7.
  32. Matsumoto F, Saitoh S, Fukui R, Kobayashi T, Tanimura N, Konno K, et al. Cathepsins are required for Toll-like receptor 9 responses. Biochem Biophys Res Commun. 2008;367(3):693–9.
  33. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi G-P, Chapman HA, et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature. 2008;456(7222):658–62.
  34. Park B, Brinkmann MM, Spooner E, Lee CC, Kim Y-M, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol. 2008;9(12):1407–414.
  35. Padrines M, Wolf M, Walz A, Baggiolini M. Interleukin-8 processing by neutrophil elastase, cathepsin G and proteinase-3. FEBS Lett. 1994;352(2):231–5.
  36. Bank U, Küpper B, Reinhold D, Hoffmann T, Ansorge S. Evidence for a crucial role of neutrophil-derived serine proteases in the inactivation of interleukin-6 at sites of inflammation. FEBS Lett. 1999;461(3):235–40.
  37. Ohashi K, Naruto M, Nakaki T, Sano E. Identification of interleukin-8 converting enzyme as cathepsin L. Biochem Biophys Acta. 2003;1649(1):30–9.
  38. Ha S-D, Martins A, Khazaie K, Han J, Chan BM, Kim SO. Cathepsin B is involved in the trafficking of TNF-{alpha}-containing vesicles to the plasma membrane in macrophages. J Immunol. 2008;181(1):690–7.
  39. Meyer-Hoffert U. Neutrophil-derived serine proteases modulate innate immune responses. Front Biosci. 2009;14:3409–18.
  40. Colbert JD, Matthews SP, Miller G, Watts C. Diverse regulatory roles for lysosomal proteases in the immune response. Eur J Immunol. 2009;39(11):2955-65.
  41. Salvesen G, Enghild JJ. An unusual specificity in the activation of neutrophil serine proteinase zymogens. Biochemistry. 1990;29(22):5304–8.
  42. Adkison AM, Raptis SZ, Kelley DG, Pham CT. Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J Clin Invest. 2002;109(3):363–71.
  43. Mallen-St. Clair J, Pham CT, Villalta SA, Caughey GH, Wolters PJ. Mast cell dipeptidyl peptidase I mediates survival from sepsis. J Clin Invest. 2004;113(4):628–34.
  44. Methot N, Guay D, Rubin J, Ethier D, Ortega K, Wong S, et al. In vivo inhibition of serine protease processing requires a high fractional inhibition of cathepsin C. Mol Pharmacol. 2008;73(6):1857–65.
  45. Honey K, Rudensky AY. Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol. 2003;3(6):472–82.
  46. Villadangos JA, Schnorrer P, Wilson NS. Control of MHC class II antigen presentation in dendritic cells: a balance between creative and destructive forces. Immunol Rev. 2005;207(1):191–205.
  47. Chapman HA. Endosomal proteases in antigen presentation. Curr Opin Immunol. 2006;18(1):78–84.
  48. Nakagawa TY, Brissette WH, Lira PD, Griffiths RJ, Petrushova N, Stock J, et al. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice. Immunity. 1999;10(2):207–17.
  49. Shi G-P, Villadangos JA, Dranoff G, Small C, Gu L, Haley KJ, et al. Cathepsin S required for normal MHC Class II peptide loading and germinal center development. Immunity. 1999;10(2):197–206.
  50. Reich M, van Swieten PF, Sommandas V, Kraus M, Fischer R, Weber E, et al. Endocytosis targets exogenous material selectively to cathepsin S in live human dendritic cells, while cell-penetrating peptides mediate nonselective transport to cysteine cathepsins. J Leukoc Biol. 2007;81(4):990–1001.
  51. Driessen C, Bryant RA, Lennon-Dumenil A-M, Villadangos JA, Bryant PW, Shi G-P, et al. Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells. J Cell Biol. 1999;147(4):775–90.
  52. Nakagawa T, Roth W, Wong P, Nelson A, Farr A, Deussing J, et al. Cathepsin L: critical role in li degradation and CD4 T cell selection in the thymus. Science. 1998;280(5362):450–3.
  53. Tolosa E, Li W, Yasuda Y, Wienhold W, Denzin LK, Lautwein A, et al. Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J Clin Invest. 2003;112(4):517–26.
  54. Kakehashi H, Nishioku T, Tsukuba T, Kadowaki T, Nakamura S, Yamamoto K. Differential regulation of the nature and functions of dendritic cells and macrophages by cathepsin E. J Immunol. 2007;179(9):5728–37.
  55. Burster T, Reich M, Zaidi N, Voelter W, Boehm BO, Kalbacher H. Cathepsin E regulates the presentation of tetanus toxin C-fragment in PMA activated primary human B cells. Biochem Biophys Res Commun. 2008;377(4):1299–303.
  56. Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P, Moura IC, et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell. 2006;126(1):205–18.
  57. Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES. Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science. 2005;307(5715):1630–4.
  58. Zou J, Henderson L, Thomas V, Swan P, Turner AN, Phelps RG. Presentation of the goodpasture autoantigen requires proteolytic unlocking steps that destroy prominent T cell epitopes. J Am Soc Nephrol. 2007;18(3):771–9.
  59. Manoury B, Mazzeo D, Fugger L, Viner N, Ponsford M, Streeter H, et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol. 2002;3(2):169–74.
  60. Burster T, Beck A, Tolosa E, Marin-Esteban V, Rotzschke O, Falk K, et al. Cathepsin G, and not the asparagine-specific endoprotease, controls the processing of myelin basic protein in lysosomes from human B lymphocytes. J Immunol. 2004;172(9):5495–503.
  61. Fiebiger E, Meraner P, Weber E, Fang IF, Stingl G, Ploegh H, et al. Cytokines regulate proteolysis in major histocompatibility complex class II-dependent antigen presentation by dendritic cells. J Exp Med. 2001;193(8):881–92.
  62. Drakesmith H, O’Neil D, Schneider SC, Binks M, Medd P, Sercarz E, et al. In vivo priming of T cells against cryptic determinants by dendritic cells exposed to interleukin 6 and native antigen. Proc Natl Acad Sci. USA 1998;95(25):14903–8.
  63. Sendide K, Deghmane A-E, Pechkovsky D, Av-Gay Y, Talal A, Hmama Z. Mycobacterium bovis BCG attenuates surface expression of mature class II molecules through IL-10-dependent inhibition of cathepsin S. J Immunol. 2005;175(8):5324–32.
  64. Pham CT, Ley TJ. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci. USA 1999;96(15):8627–32.
  65. Sutton VR, Waterhouse NJ, Browne KA, Sedelies K, Ciccone A, Anthony D, et al. Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis. J Cell Biol. 2007;176(4):425–33.
  66. Ondr JK, Pham CT. Characterization of murine cathepsin W and its role in cell-mediated cytotoxicity. J Biol Chem. 2004;279(26):27525–33.
  67. Michallet M-C, Saltel F, Preville X, Flacher M, Revillard J-P, Genestier L. Cathepsin B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion. Blood. 2003;102(10):3719–26.
  68. Michallet M-C, Saltel F, Flacher M, Revillard J-P, Genestier L. Cathepsin-dependent apoptosis triggered by supraoptimal activation of T lymphocytes: a possible mechanism of high dose tolerance. J Immunol. 2004;172(9):5405–14.
  69. Kishimoto H, Sprent J. Strong TCR ligation without costimulation causes rapid onset of Fas-dependent apoptosis of naive murine CD4+ T cells. J Immunol. 1999;163(4):1817–26.
  70. Alexander-Miller MA, Leggatt GR, Sarin A, Berzofsky JA. Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL. J Exp Med. 1996;184(2):485–92.
  71. van Eijk M, de Groot C. Germinal center B cell apoptosis requires both caspase and cathepsin activity. J Immunol. 1999;163(5):2478–82.
  72. van Nierop K, Muller FJ, Stap J, Van Noorden CJ, van Eijk M, de Groot C. Lysosomal destabilization contributes to apoptosis of germinal center B-lymphocytes. J Histochem Cytochem. 2006;54(12):1425–35.
  73. Laforge M, Petit F, Estaquier J, Senik A. Commitment to apoptosis in CD4+ T lymphocytes productively infected with human immunodeficiency virus type 1 is initiated by lysosomal membrane permeabilization, itself induced by the isolated expression of the viral protein Nef. J Virol. 2007;81(20):11426–40.
  74. Reddy VY, Zhang QY, Weiss SJ. Pericellular mobilization of the tissue-destructive cysteine proteases, cathepsin B, L and S, by human monocyte-derived macrophages. Proc Natl Acad Sci. USA 1995;92(9):3849–53.
  75. Thurmond RL, Sun S, Karlsson L, Edwards JP. Cathepsin S inhibitors as novel immunomodulators. Curr Opin Investig Drugs. 2005;6(5):473–82.
  76. Pierre P, Mellman I. Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells. Cell. 1998;93(7):1135–45.
  77. Roth W, Deussing JA, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A, et al. Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J. 2000;14(13):2075–86.
  78. Hagemann S, Günther T, Dennemärker J, Lohmüller T, Brömme D, Schüle R, et al. The human cysteine protease cathepsin V can compensate for murine cathepsin L in mouse epidermis and hair follicles. Eur J Cell Biol. 2004;83(11-12):775–80.
  79. Stypmann J, Gläser K, Roth W, Tobin DJ, Petermann I, Matthias R, et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc Natl Acad Sci. USA 2002;99(9):6234–9.
  80. Liu J, Sukhova GK, Yang J-T, Sun J, Ma L, Ren A, et al. Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells. Atherosclerosis. 2006;184(2):302–11.
  81. Kitamoto S, Sukhova GK, Sun J, Yang M, Libby P, Love V, et al. Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice. Circulation. 2007;115(15):2065–75.
  82. Sevenich L, Pennacchio LA, Peters C, Reinheckel T. Human cathepsin L rescues the neurodegeneration and lethality in cathepsin B/L double-deficient mice. Biol Chem. 2006;387(7):885–91.
  83. Everts V, Korper W, Hoeben KA, Jansen ID, Bromme D, Cleutjens KB, et al. Osteoclastic bone degradation and the role of different cysteine proteinases and matrix metalloproteinases: differences between calvaria and long bone. J Bone Miner Res. 2006;21(9):1399–408.
  84. Tsukuba T, Okamoto K, Okamoto Y, Yanagawa M, Kohmura K, Yasuda Y, et al. Association of cathepsin E deficiency with development of atopic dermatitis. J Biochem. 2003;134(6): 893–902.
  85. Henningsson F, Yamamoto K, Saftig P, Reinheckel T, Peters C, Knight SD, et al. A role for cathepsin E in the processing of mast-cell carboxypeptidase A. J Cell Sci. 2005;118(9):2035–42.
  86. Yasuda Y, Kaleta J, Brömme D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev. 2005;57(7):973–93.
  87. Grabowska U, Chambers TJ, Shiroo M. Recent development in cathepsin K inhibitor design. Curr Opin Drug Discov Devel. 2005;8(5):619–30.
  88. Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain. 2006;129(6):1438–45.
  89. Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Brück W, et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78(6):988–98.
  90. Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen J, et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease. Neuron. 2006;51(6):703–14.
  91. Benes P, Vetvicka V, Fusek M. Cathepsin D – many functions of one aspartic protease. Crit Rev Oncol Hematol. 2008;68(1):12–28.
  92. Pagano MB, Bartoli MA, Ennis TL, Mao D, Simmons PM, Thompson RW, et al. Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms. Proc Natl Acad Sci. 2007;104(8):2855–60.
  93. Hu Y, Pham CT. Dipeptidyl peptidase I regulates the development of collagen-induced arthritis. Arthritis Rheum. 2005;52(8):2553–8.
  94. Pham CT, Ivanovich JL, Raptis SZ, Zehnbauer B, Ley TJ. Papillon-Lefèvre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J Immunol. 2004;173(12):7277–81.
  95. Jäättelä M. Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene. 2004;23(16):2746–56.
  96. Kirkegaard T, Jäättelä M. Lysosomal involvement in cell death and cancer. Biochem Biophys Acta. 2009;1793(4):746–54.
  97. Pennacchio LA, Lehesjoki AE, Stone NE, Willour VL, Virtaneva K, Miao J, et al. Mutations in the gene encoding cystatin B in progressive myoclonous epilepsy (EPM1). Science. 1996;271(5256):1731–4.
  98. Pennacchio LA, Bouley DM, Higgins KM, Scott MP, Noebels JL, Myers RM. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet. 1998;20(3):251–8.
  99. Farina F, Cappello F, Todaro M, Bucchieri F, Peri G, Zummo G, et al. Involvement of caspase-3 and GD3 ganglioside in ceramide-induced apoptosis in Farber disease. J Histochem Cytochem. 2000;48(1):57–62.