Glutathione peroxidases (GPXs) are enzymes present in almost all organisms with the primary function of limiting peroxides 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 (MAM) 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, whilst 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.

Regulation of calcium fluxes by GPX8, a type-II transmembrane peroxidase enriched at the mitochondria-associated endoplasmic reticulum membrane

RIMESSI, Alessandro;PINTON, Paolo;
2017

Abstract

Glutathione peroxidases (GPXs) are enzymes present in almost all organisms with the primary function of limiting peroxides 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 (MAM) 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, whilst 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.
2017
Yoboue, Ed; Rimessi, Alessandro; Anelli, T; Pinton, Paolo; Sitia, R.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2363651
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