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8.A.131.  The Transmembrane Protease Serine (TMPRSS) Family 

TMPRSS3 is a serine protease that plays a role in hearing. It acts as a permissive factor for cochlear hair cell survival and activation at the onset of hearing and is required for saccular hair cell survival. It activates ENaC channels (Guipponi et al. 2002). Important signaling pathways in the inner ear are controlled by proteolytic cleavage and suggest: (i) the existence of an auto-catalytic processing by which TMPRSS3 becomes active, and (ii) that ENaC is a substrate of TMPRSS3 in the inner ear. Missense mutations in TMPRSS3 greatly diminish the proteolytic activity of TMPRSS3, and this explains the importance of the protease in nonsyndromic hearing loss (NSHL) (Wong et al. 2020).

Corin of Homo sapiens is a protease of 1042 aas with an N-terminal TMS, also called atrial natriuretic peptide-converting enzyme. It is a serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing (Yan et al. 2000, Jiang et al. 2011, Peng et al. 2011). It converts through proteolytic cleavage the non-functional propeptides NPPA and NPPB into their active hormones, ANP and BNP(1-32), respectively, thereby regulating blood pressure in the heart and promoting natriuresis, diuresis and vasodilation (Yan et al. 2000). Proteolytic cleavage of pro-NPPA also plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus (Cui et al. 2012). CRN also acts as a regulator of sodium reabsorption in the kidney. It is inhibited in a dose-dependent manner by non-specific trypsin-like serine protease inhibitors including benzamidine. It regulates electrolyte homeostasis in eccrine sweat glands (He et al. 2021).


This family belongs to the: MACPF/TMPRSS/SelP-R Superfamily.

References associated with 8.A.131 family:

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Chen, Y., W.C. Huang, C.S. Yang, F.J. Cheng, Y.F. Chiu, H.F. Chen, T.K. Huynh, C.F. Huang, C.H. Chen, H.C. Wang, and M.C. Hung. (2021). Screening strategy of TMPRSS2 inhibitors by FRET-based enzymatic activity for TMPRSS2-based cancer and COVID-19 treatment. Am J Cancer Res 11: 827-836. 33791156
Cui, Y., W. Wang, N. Dong, J. Lou, D.K. Srinivasan, W. Cheng, X. Huang, M. Liu, C. Fang, J. Peng, S. Chen, S. Wu, Z. Liu, L. Dong, Y. Zhou, and Q. Wu. (2012). Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. Nature 484: 246-250. 22437503
Fang, J.D., H.H. Tung, and S.L. Lee. (2019). Mitochondrial localization of St14-encoding transmembrane serine protease is involved in neural stem/progenitor cell bioenergetics through binding to FF-ATP synthase complex. FASEB J. 33: 4327-4340. 30566397
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Guipponi, M., G. Vuagniaux, M. Wattenhofer, K. Shibuya, M. Vazquez, L. Dougherty, N. Scamuffa, E. Guida, M. Okui, C. Rossier, M. Hancock, K. Buchet, A. Reymond, E. Hummler, P.L. Marzella, J. Kudoh, N. Shimizu, H.S. Scott, S.E. Antonarakis, and B.C. Rossier. (2002). The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum Mol Genet 11: 2829-2836. 12393794
He, M., T. Zhou, Y. Niu, W. Feng, X. Gu, W. Xu, S. Zhang, Z. Wang, Y. Zhang, C. Wang, L. Dong, M. Liu, N. Dong, and Q. Wu. (2021). The protease corin regulates electrolyte homeostasis in eccrine sweat glands. PLoS Biol 19: e3001090. 33591965
Herter, S., D.E. Piper, W. Aaron, T. Gabriele, G. Cutler, P. Cao, A.S. Bhatt, Y. Choe, C.S. Craik, N. Walker, D. Meininger, T. Hoey, and R.J. Austin. (2005). Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers. Biochem. J. 390: 125-136. 15839837
Heurich, A., H. Hofmann-Winkler, S. Gierer, T. Liepold, O. Jahn, and S. Pöhlmann. (2014). TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J. Virol. 88: 1293-1307. 24227843
Icho, S., E. Rujas, K. Muthuraman, J. Tam, H. Liang, S. Landreth, M. Liao, D. Falzarano, J.P. Julien, and R.A. Melnyk. (2022). Dual Inhibition of Vacuolar-ATPase and TMPRSS2 Is Required for Complete Blockade of SARS-CoV-2 Entry into Cells. Antimicrob. Agents Chemother. 66: e0043922. 35703551
Jiang, J., S. Wu, W. Wang, S. Chen, J. Peng, X. Zhang, and Q. Wu. (2011). Ectodomain shedding and autocleavage of the cardiac membrane protease corin. J. Biol. Chem. 286: 10066-10072. 21288900
Lunger, L., M. Retz, M. Bandur, M. Souchay, E. Vitzthum, M. Jäger, G. Weirich, T. Schuster, M. Autenrieth, H. Kübler, T. Maurer, M. Thalgott, K. Herkommer, F. Koll, J.E. Gschwend, R. Nawroth, and M.M. Heck. (2020). KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy. Prostate Cancer Prostatic Dis. [Epub: Ahead of Print] 32978525
Malik, J.R., A. Acharya, S.N. Avedissian, S.N. Byrareddy, C.V. Fletcher, A.T. Podany, and S.R. Dyavar. (2023). ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics. Int J Mol Sci 24:. 37239978
Martin, C.E., A.S. Murray, K.E. Sala-Hamrick, J.R. Mackinder, E.C. Harrison, J.G. Lundgren, F.A. Varela, and K. List. (2021). Posttranslational modifications of serine protease TMPRSS13 regulate zymogen activation, proteolytic activity, and cell surface localization. J. Biol. Chem. 297: 101227. 34562451
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Tang, P.C., A.L. Alex, J. Nie, J. Lee, A.A. Roth, K.T. Booth, K.R. Koehler, E. Hashino, and R.F. Nelson. (2019). Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids. Stem Cell Reports 13: 147-162. 31204303
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Weiss, J., G. Bajraktari-Sylejmani, and W.E. Haefeli. (2021). Low risk of the TMPRSS2 inhibitor camostat mesylate and its metabolite GBPA to act as perpetrators of drug-drug interactions. Chem Biol Interact 338: 109428. 33647240
Wong, S.H., Y.C. Yen, S.Y. Li, and J.J. Yang. (2020). Novel Mutations in the TMPRSS3 Gene may Contribute to Taiwanese Patients with Nonsyndromic Hearing Loss. Int J Mol Sci 21:. 32235586
Yan, W., F. Wu, J. Morser, and Q. Wu. (2000). Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme. Proc. Natl. Acad. Sci. USA 97: 8525-8529. 10880574
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Zhang, Z.W., B. Pang, Y.C. Chen, and A.Q. Peng. (2019). TMPRSS3 regulates cell viability and apoptosis processes of HEI-OC1 cells via regulation of the circ-Slc4a2, miR-182 and Akt cascade. J Gene Med 21: e3118. 31408246