Edgar Djaha Yoboue1, Alessandro Rimessi2, Tiziana Anelli1,3, Paolo Pinton2, Roberto Sitia1,3. 1. 1 Protein Transport and Secretion Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele , Milan, Italy . 2. 2 Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), Department of Morphology, Surgery and Experimental Medicine, University of Ferrara , Ferrara, Italy . 3. 3 Vita-Salute San Raffaele University, School of Medicine, Milan, Italy .
Abstract
Glutathione peroxidases (GPXs) are enzymes that are present in almost all organisms with the primary function of limiting peroxide accumulation. In mammals, two of the eight members (GPX7 and GPX8) reside in the endoplasmic reticulum (ER). A peculiar feature of GPX8 is the concomitant presence of a conserved N-terminal transmembrane domain (TMD) and a C-terminal KDEL-like motif for ER localization. AIMS: Investigating whether and how GPX8 impacts Ca2+ homeostasis and signaling. RESULTS: We show that GPX8 is enriched in mitochondria-associated membranes and regulates Ca2+ storage and fluxes. Its levels correlate with [Ca2+]ER, and cytosolic and mitochondrial Ca2+ fluxes. GPX7, which lacks a TMD, does not share these properties. Deleting or replacing the GPX8 TMD with an unrelated N-terminal membrane integration sequence abolishes all effects on Ca2+ fluxes, whereas appending the GPX8 TMD to GPX7 transfers the Ca2+-regulating properties. Innovation and Conclusion: The notion that the TMD of GPX8, in addition to its enzymatic activity, is essential for regulating Ca2+ dynamics reveals a novel level of integration between redox-related proteins and Ca2+ signaling/homeostasis. Antioxid. Redox Signal. 27, 583-595.
Glutathione peroxidases (GPXs) are enzymes that are present in almost all organisms with the primary function of limiting peroxide accumulation. In mammals, two of the eight members (GPX7 and GPX8) reside in the endoplasmic reticulum (ER). A peculiar feature of GPX8 is the concomitant presence of a conserved N-terminal transmembrane domain (TMD) and a C-terminal KDEL-like motif for ER localization. AIMS: Investigating whether and how GPX8 impacts Ca2+ homeostasis and signaling. RESULTS: We show that GPX8 is enriched in mitochondria-associated membranes and regulates Ca2+ storage and fluxes. Its levels correlate with [Ca2+]ER, and cytosolic and mitochondrial Ca2+ fluxes. GPX7, which lacks a TMD, does not share these properties. Deleting or replacing the GPX8TMD with an unrelated N-terminal membrane integration sequence abolishes all effects on Ca2+ fluxes, whereas appending the GPX8TMD to GPX7 transfers the Ca2+-regulating properties. Innovation and Conclusion: The notion that the TMD of GPX8, in addition to its enzymatic activity, is essential for regulating Ca2+ dynamics reveals a novel level of integration between redox-related proteins and Ca2+ signaling/homeostasis. Antioxid. Redox Signal. 27, 583-595.
Authors: Anees Khatib; Balakrishnan Solaimuthu; Michal Ben Yosef; Areej Abu Rmaileh; Mayur Tanna; Gidi Oren; Michal Schlesinger Frisch; Jonathan H Axelrod; Michal Lichtenstein; Yoav D Shaul Journal: Proc Natl Acad Sci U S A Date: 2020-08-18 Impact factor: 11.205