title: Regulation of Calcium Fluxes by GPX8, a Type-II Transmembrane Peroxidase Enriched at the Mitochondria-Associated Endoplasmic Reticulum Membrane.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 1 Protein Transport and Secretion Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele , Milan, Italy .
authors.forename: Edgar Djaha
authors.initials: ED
authors.lastname: Yoboue
authors.affiliation: 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 .
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rimessi
authors.affiliation: 1 Protein Transport and Secretion Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele , Milan, Italy .|3 Vita-Salute San Raffaele University, School of Medicine, Milan, Italy .
authors.forename: Tiziana
authors.initials: T
authors.lastname: Anelli
authors.affiliation: 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 .
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: 1 Protein Transport and Secretion Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele , Milan, Italy .|3 Vita-Salute San Raffaele University, School of Medicine, Milan, Italy .
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010544:Peroxidases / Q000737:chemistry / Q000378:metabolism*; D000072417:Protein Domains
chemical_list: C558642:GPX8 protein, human; D010544:Peroxidases; D002118:Calcium
keywords: calcium (Ca2+) signaling; endoplasmic reticulum; glutathione peroxidases; membrane topology; mitochondria associated membrane (MAM)