title: SEPN1, an endoplasmic reticulum-localized selenoprotein linked to skeletal muscle pathology, counteracts hyperoxidation by means of redox-regulating SERCA2 pump activity.
abstract: Selenoprotein N (SEPN1) is a broadly expressed resident protein of the endoplasmic reticulum (ER) whose loss-of-function inexplicably leads to human muscle disease. We found that SEPN1 levels parallel those of endoplamic reticulum oxidoreductin 1 (ERO1), an ER protein thiol oxidase, and that SEPN1's redox activity defends the ER from ERO1-generated peroxides. Moreover, we have defined the redox-regulated interactome of SEPN1 and identified the ER calcium import SERCA2 pump as a redox-partner of SEPN1. SEPN1 enhances SERCA2 activity by reducing luminal cysteines that are hyperoxidized by ERO1-generated peroxides. Cells lacking SEPN1 are hypersensitive to ERO1 overexpression and conspicuously defective in ER calcium re-uptake. After being muscle-transduced with an adeno-associated virus driving ERO1α, SEPN1 knockout mice unmasks a myopathy that resembles the dense core disease due to human mutations in SEPN1, whereas the combined attenuation of ERO1α and SEPN1 enhances cell fitness. These observations reveal the involvement of SEPN1 in ER redox and calcium homeostasis and that an ERO1 inhibitor, restoring redox-dependent calcium homeostasis, may ameliorate the myopathy of SEPN1 deficiency.
authors.affiliation: Dulbecco Telethon Institute at IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Marino
authors.affiliation: Dulbecco Telethon Institute at IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Stoilova
authors.affiliation: 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: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Cattaneo
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, and Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.affiliation: 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: Dulbecco Telethon Institute at IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, ester.zito@marionegri.it.
authors.forename: Ester
authors.initials: E
authors.lastname: Zito
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D010545:Peroxides; C545253:SEPN1 protein, mouse; D051140:Selenoproteins; D010088:Oxidoreductases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D003545:Cysteine