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TMPRSS13 zymogen activation, surface localization, and shedding is regulated by proteolytic cleavage within the non-catalytic stem region

  • Carly E. Martin , Andrew S. Murray , Jacob R. Mackinder , Kimberley E. Sala-Hamrick , Michael G. Flynn , Joseph G. Lundgren , Fausto A. Varela and Karin List EMAIL logo
Published/Copyright: July 8, 2022
Biological Chemistry
From the journal Biological Chemistry Volume 403 Issue 10

Abstract

TMPRSS13 is a member of the type II transmembrane serine protease (TTSP) family. Here we characterize a novel post-translational mechanism important for TMPRSS13 function: proteolytic cleavage within the extracellular TMPRSS13 stem region located between the transmembrane domain and the first site of N-linked glycosylation at asparagine (N)-250 in the scavenger receptor cysteine rich (SRCR) domain. Importantly, the catalytic competence of TMPRSS13 is essential for stem region cleavage, suggesting an autonomous mechanism of action. Site-directed mutagenesis of the 10 basic amino acids (four arginine and six lysine residues) in this region abrogated zymogen activation and catalytic activity of TMPRSS13, as well as phosphorylation, cell surface expression, and shedding. Mutation analysis of individual arginine residues identified R223, a residue located between the low-density lipoprotein receptor class A domain and the SRCR domain, as important for stem region cleavage. Mutation of R223 causes a reduction in the aforementioned functional processing steps of TMPRSS13. These data provide further insight into the roles of different post-translational modifications as regulators of the function and localization of TMPRSS13. Additionally, the data suggest the presence of complex interconnected regulatory mechanisms that may serve to ensure the proper levels of cell-surface and pericellular TMPRSS13-mediated proteolysis under homeostatic conditions.

Keywords: cell-surface serine protease; MSPL; TMPRSS13; TTSP; type II transmembrane serine protease; zymogen activation
Corresponding author: Karin List, Department of Pharmacology, Wayne State University, 540 East Canfield, Detroit, MI 48201, USA; and Department of Oncology, Wayne State University, 540 East Canfield, Detroit, MI 48201, USA, E-mail:

Funding source: DeRoy Testamentary Foundation

Funding source: National Cancer Institute 10.13039/100000054

Award Identifier / Grant number: R01CA160565, R01CA160565-04S, R01CA222359, T32-CA009531

Acknowledgments

We thank Drs. Izabela Podgorski and Heather Gibson, Wayne State University, for critically reading the manuscript and providing input.

  1. Author contributions: CEM and KL conceived the idea of the study and planned the experiments. CEM performed the majority of the experiments. ASM, MGF, JGL, KSH, and JRM, and FAV assisted with plasmid construction, cell line maintenance, transfections, and western blot analysis. CEM and KL wrote the manuscript and prepared the figures. All authors contributed to interpretation and discussion of the results and read, edited, and approved the final version.

  2. Research funding: This work was supported by NIH/NCI R01CA160565 grant (K.L.), NIH/NCI R01CA160565-04S grant (K.L., F.A.V.), NIH/NCI R01CA222359 (K.L), NIH Ruth L. Kirschstein National Research Service Award T32-CA009531 (A.S.M. and C.E.M) and The DeRoy Testamentary Foundation (A.S.M. and C.E.M). The Microscopy, Imaging, and Cytometry Resources Core is supported, in part, by NIH Center grants P30 CA22453 to the Karmanos Cancer Institute and R50 CA251068-01 to Dr. Moin, Wayne State University, and the Perinatology Research Branch of the National Institutes of Child Health and Development. We thank Drs. Izabela Podgorski and Heather Gibson, Wayne State University, for critically reading the manuscript and providing input.

  3. Conflict of interest statement: The authors declare that they have no conflicts of interest with the contents of this article.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2022-0129).

Received: 2022-02-28
Accepted: 2022-05-24
Published Online: 2022-07-08
Published in Print: 2022-09-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Research Articles/Short Communications
  3. Cell Biology and Signaling
  4. Diselenide-derivative of 3-pyridinol targets redox enzymes leading to cell cycle deregulation and apoptosis in A549 cells
  5. NF90/NFAR (nuclear factors associated with dsRNA) – a new methylation substrate of the PRMT5-WD45-RioK1 complex
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  9. L-theanine induces skeletal muscle fiber type transformation by activation of prox1/CaN signaling pathway in C2C12 myotubes
  10. Proteolysis
  11. TMPRSS13 zymogen activation, surface localization, and shedding is regulated by proteolytic cleavage within the non-catalytic stem region
https://doi.org/10.1515/hsz-2022-0129
Keywords for this article
cell-surface serine protease; MSPL; TMPRSS13; TTSP; type II transmembrane serine protease; zymogen activation

Articles in the same Issue

  1. Frontmatter
  2. Research Articles/Short Communications
  3. Cell Biology and Signaling
  4. Diselenide-derivative of 3-pyridinol targets redox enzymes leading to cell cycle deregulation and apoptosis in A549 cells
  5. NF90/NFAR (nuclear factors associated with dsRNA) – a new methylation substrate of the PRMT5-WD45-RioK1 complex
  6. PHF20L1 mediates PAX2 expression to promote angiogenesis and liver metastasis in colorectal cancer through regulating HIC1
  7. Nitazoxanide inhibits osteosarcoma cells growth and metastasis by suppressing AKT/mTOR and Wnt/β-catenin signaling pathways
  8. LncRNA-p21 suppresses cell proliferation and induces apoptosis in gastric cancer by sponging miR-514b-3p and up-regulating ARHGEF9 expression
  9. L-theanine induces skeletal muscle fiber type transformation by activation of prox1/CaN signaling pathway in C2C12 myotubes
  10. Proteolysis
  11. TMPRSS13 zymogen activation, surface localization, and shedding is regulated by proteolytic cleavage within the non-catalytic stem region
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