The intramembrane proteases SPPL2a and SPPL2b regulate the homeostasis of selected SNARE proteins.

Autor: Ballin M; Biochemical Institute, Christian Albrechts University Kiel, Kiel, Germany.; Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany., Griep W; Biochemical Institute, Christian Albrechts University Kiel, Kiel, Germany.; Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany., Patel M; Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany., Karl M; Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany., Mentrup T; Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany., Rivera-Monroy J; Department of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany., Foo B; Department of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany., Schwappach B; Department of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany., Schröder B; Institute of Physiological Chemistry, Technische Universität Dresden, Dresden, Germany.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2023 May; Vol. 290 (9), pp. 2320-2337. Date of Electronic Publication: 2022 Sep 13.
DOI: 10.1111/febs.16610
Abstrakt: Signal peptide peptidase (SPP) and SPP-like (SPPL) aspartyl intramembrane proteases are known to contribute to sequential processing of type II-oriented membrane proteins referred to as regulated intramembrane proteolysis. The ER-resident family members SPP and SPPL2c were shown to also cleave tail-anchored proteins, including selected SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins facilitating membrane fusion events. Here, we analysed whether the related SPPL2a and SPPL2b proteases, which localise to the endocytic or late secretory pathway, are also able to process SNARE proteins. Therefore, we screened 18 SNARE proteins for cleavage by SPPL2a and SPPL2b based on cellular co-expression assays, of which the proteins VAMP1, VAMP2, VAMP3 and VAMP4 were processed by SPPL2a/b demonstrating the capability of these two proteases to proteolyse tail-anchored proteins. Cleavage of the four SNARE proteins was scrutinised at the endogenous level upon SPPL2a/b inhibition in different cell lines as well as by analysing VAMP1-4 levels in tissues and primary cells of SPPL2a/b double-deficient (dKO) mice. Loss of SPPL2a/b activity resulted in an accumulation of VAMP1-4 in a cell type- and tissue-dependent manner, identifying these proteins as SPPL2a/b substrates validated in vivo. Therefore, we propose that SPPL2a/b control cellular levels of VAMP1-4 by initiating the degradation of these proteins, which might impact cellular trafficking.
(© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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