Kidney-Specific Membrane-Bound Serine Proteases CAP1/Prss8 and CAP3/St14 Affect ENaC Subunit Abundances but Not Its Activity

Elodie Ehret; Sévan Stroh; Muriel Auberson; Frédérique Ino; Yannick Jäger; Marc Maillard; Roman Szabo; Thomas H Bugge; Simona Frateschi; Edith Hummler

doi:10.3390/cells12192342

Kidney-Specific Membrane-Bound Serine Proteases CAP1/Prss8 and CAP3/St14 Affect ENaC Subunit Abundances but Not Its Activity

Cells. 2023 Sep 23;12(19):2342. doi: 10.3390/cells12192342.

Authors

Elodie Ehret^{1

2}, Sévan Stroh¹, Muriel Auberson¹, Frédérique Ino^{1

3}, Yannick Jäger^{1

4}, Marc Maillard⁵, Roman Szabo⁶, Thomas H Bugge⁶, Simona Frateschi¹, Edith Hummler^{1

2}

Affiliations

¹ Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, Switzerland.
² National Center of Competence in Research "Kidney.CH", 1011 Lausanne, Switzerland.
³ Department of Medicine, University of Geneva, 1211 Geneva, Switzerland.
⁴ Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
⁵ Service of Nephrology, Department of Medicine, Lausanne University Hospital (CHUV), 1005 Lausanne, Switzerland.
⁶ National Institutes of Health/NIDCR, Bethesda, MD 20892, USA.

Abstract

The serine proteases CAP1/Prss8 and CAP3/St14 are identified as ENaC channel-activating proteases in vitro, highly suggesting that they are required for proteolytic activation of ENaC in vivo. The present study tested whether CAP3/St14 is relevant for renal proteolytic ENaC activation and affects ENaC-mediated Na⁺ absorption following Na⁺ deprivation conditions. CAP3/St14 knockout mice exhibit a significant decrease in CAP1/Prss8 protein expression with altered ENaC subunit and decreased pNCC protein abundances but overall maintain sodium balance. RNAscope-based analyses reveal co-expression of CAP3/St14 and CAP1/Prss8 with alpha ENaC in distal tubules of the cortex from wild-type mice. Double CAP1/Prss8; CAP3/St14-deficiency maintained Na⁺ and K⁺ balance on a Na⁺-deprived diet, restored ENaC subunit protein abundances but showed reduced NCC activity under Na⁺ deprivation. Overall, our data clearly show that CAP3/St14 is not required for direct proteolytic activation of ENaC but for its protein abundance. Our study reveals a complex regulation of ENaC by these serine proteases on the expression level rather than on its proteolytic activation.

Keywords: CAP1/Prss8; CAP3/St14; proteolytic ENaC activation; sodium and potassium balance.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Epithelial Sodium Channels* / metabolism
Kidney
Mice
Serine Proteases*

Substances

Serine Proteases
prostasin
St14 protein, mouse
Epithelial Sodium Channels

Grants and funding

This research was funded by the Swiss National Science Foundation (31003A-182478/1) and the National Center of Competence in Research program (NCCR, N-403-07-23). Thomas H. Bugge and Romain Szabo were supported by the Intramural Research Program at the National Institute of Dental and Craniofacial Research, NIH, USA.