Specialized Roles for Cysteine Cathepsins in Health and Disease

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2010 Oct 6

PMID 20921628

Citations 250

Authors

Jochen Reiser

Brian Adair

Thomas Reinheckel

Affiliations

Soon will be listed here.

Abstract

Cathepsins were originally identified as proteases that act in the lysosome. Recent work has uncovered nontraditional roles for cathepsins in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized cathepsins participate in many physiologic and pathophysiologic cellular processes, in which they can act as both digestive and regulatory proteases. In this review, we discuss the transcriptional and translational control of cathepsin expression, the regulation of intracellular sorting of cathepsins, and the structural basis of cathepsin activation and inhibition. In particular, we highlight the emerging roles of various cathepsin forms in disease, particularly those of the cardiac and renal systems.

Citing Articles

Circulating proteomic biomarkers for cerebral amyloid angiopathy screening and risk stratification.

Xu J, Su Y, Sha Y, Fu J, Yan T, Xu F Alzheimers Dement. 2025; 21(3):e70044.

PMID: 40042503 PMC: 11881623. DOI: 10.1002/alz.70044.

Non-Canonical, Extralysosomal Activities of Lysosomal Peptidases in Physiological and Pathological Conditions: New Clinical Opportunities for Cancer Therapy.

Conesa-Bakkali R, Morillo-Huesca M, Martinez-Fabregas J Cells. 2025; 14(2).

PMID: 39851495 PMC: 11763575. DOI: 10.3390/cells14020068.

Association between cathepsins and cardiomyopathy: A Mendelian randomization study.

Chen Q, Yang X, Zhang Q, Yu Z Medicine (Baltimore). 2024; 103(51):e40974.

PMID: 39705476 PMC: 11666145. DOI: 10.1097/MD.0000000000040974.

Elevated Cathepsin B enzyme levels: a potential risk indicator for rheumatoid arthritis: Insights from a Mendelian randomization study.

Hou R, Liu X, Zhang C, Cai S, Liu C, Huang Q Medicine (Baltimore). 2024; 103(50):e40988.

PMID: 39686441 PMC: 11651435. DOI: 10.1097/MD.0000000000040988.

Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence.

Chang S, Moon R, Nam D, Lee S, Yoon I, Lee D Nucleic Acids Res. 2024; 53(3).

PMID: 39660649 PMC: 11797049. DOI: 10.1093/nar/gkae1210.

References

Hinkes B, Wiggins R, Gbadegesin R, Vlangos C, Seelow D, Nurnberg G . Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006; 38(12):1397-405. DOI: 10.1038/ng1918. View

Braulke T, Bonifacino J . Sorting of lysosomal proteins. Biochim Biophys Acta. 2008; 1793(4):605-14. DOI: 10.1016/j.bbamcr.2008.10.016. View

Barrett A, Rawlings N . 'Species' of peptidases. Biol Chem. 2007; 388(11):1151-7. DOI: 10.1515/BC.2007.151. View

van Acker G, Saluja A, Bhagat L, Singh V, Song A, Steer M . Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity. Am J Physiol Gastrointest Liver Physiol. 2002; 283(3):G794-800. DOI: 10.1152/ajpgi.00363.2001. View

Tao K, Stearns N, Dong J, Wu Q, Sahagian G . The proregion of cathepsin L is required for proper folding, stability, and ER exit. Arch Biochem Biophys. 1994; 311(1):19-27. DOI: 10.1006/abbi.1994.1203. View

Hwang S, Garza C, Mosier C, Toneff T, Wunderlich E, Goldsmith P . Cathepsin L expression is directed to secretory vesicles for enkephalin neuropeptide biosynthesis and secretion. J Biol Chem. 2007; 282(13):9556-9563. DOI: 10.1074/jbc.M605510200. View

Gondi C, Lakka S, Yanamandra N, Olivero W, Dinh D, Gujrati M . Adenovirus-mediated expression of antisense urokinase plasminogen activator receptor and antisense cathepsin B inhibits tumor growth, invasion, and angiogenesis in gliomas. Cancer Res. 2004; 64(12):4069-77. DOI: 10.1158/0008-5472.CAN-04-1243. View

Baranski T, Faust P, Kornfeld S . Generation of a lysosomal enzyme targeting signal in the secretory protein pepsinogen. Cell. 1990; 63(2):281-91. DOI: 10.1016/0092-8674(90)90161-7. View

Gocheva V, Zeng W, Ke D, Klimstra D, Reinheckel T, Peters C . Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev. 2006; 20(5):543-56. PMC: 1410800. DOI: 10.1101/gad.1407406. View

10.

Lerch M, Saluja A, Runzi M, Dawra R, Steer M . Luminal endocytosis and intracellular targeting by acinar cells during early biliary pancreatitis in the opossum. J Clin Invest. 1995; 95(5):2222-31. PMC: 295834. DOI: 10.1172/JCI117912. View

11.

Mason R . Emerging functions of placental cathepsins. Placenta. 2008; 29(5):385-90. DOI: 10.1016/j.placenta.2008.02.006. View

12.

Hornung V, Bauernfeind F, Halle A, Samstad E, Kono H, Rock K . Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008; 9(8):847-56. PMC: 2834784. DOI: 10.1038/ni.1631. View

13.

Akbar H, Cancelas J, Williams D, Zheng J, Zheng Y . Rational design and applications of a Rac GTPase-specific small molecule inhibitor. Methods Enzymol. 2006; 406:554-65. DOI: 10.1016/S0076-6879(06)06043-5. View

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(4):387-403. DOI: 10.2174/138161207780162962. View

15.

Duncan E, Muratore-Schroeder T, Cook R, Garcia B, Shabanowitz J, Hunt D . Cathepsin L proteolytically processes histone H3 during mouse embryonic stem cell differentiation. Cell. 2008; 135(2):284-94. PMC: 2579750. DOI: 10.1016/j.cell.2008.09.055. View

16.

Schilling K, Korner A, Sehmisch S, Kreusch A, Kleint R, Benedix Y . Selectivity of propeptide-enzyme interaction in cathepsin L-like cysteine proteases. Biol Chem. 2008; 390(2):167-74. DOI: 10.1515/BC.2009.023. View

17.

Hagemann S, Gunther T, Dennemarker J, Lohmuller T, Bromme D, Schule R . The human cysteine protease cathepsin V can compensate for murine cathepsin L in mouse epidermis and hair follicles. Eur J Cell Biol. 2005; 83(11-12):775-80. DOI: 10.1078/0171-9335-00404. View

18.

Tang Q, Cai J, Shen D, Bian Z, Yan L, Wang Y . Lysosomal cysteine peptidase cathepsin L protects against cardiac hypertrophy through blocking AKT/GSK3beta signaling. J Mol Med (Berl). 2008; 87(3):249-60. DOI: 10.1007/s00109-008-0423-2. View

19.

Toomes C, James J, Wood A, Wu C, McCormick D, Lench N . Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet. 1999; 23(4):421-4. DOI: 10.1038/70525. View

20.

Mareninova O, Hermann K, French S, OKonski M, Pandol S, Webster P . Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J Clin Invest. 2009; 119(11):3340-55. PMC: 2769194. DOI: 10.1172/JCI38674. View