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.

Endoplasmic Reticulum Oxidative Stress Triggers Tgf-Beta-Dependent Muscle Dysfunction by Accelerating Ascorbic Acid Turnover

“…In order to characterise the chain of events that can connect a hyperoxidised ER to a hyperactive TGF-beta signalling that does not cause fibrosis, we used a cell system of SEPN1 knock-down (SEPN1 KD) C2C12 myoblasts16 (Fig. 3A).…”

“…However, despite its ubiquitous expression, the loss-of-function mutation leads to rare early-onset recessive neuromuscular disorders. It has also been shown that SEPN1 knock-out (KO) mice are particularly sensitive to ER hyperoxidation as we have previously found that the over-expression of ERO1 is sufficient to compromise muscle function in SEPN1 KO but not in wild-type (WT) mice16.…”

Dietary selenium augments sarcoplasmic calcium release and mechanical performance in mice

“…SelN can also regulate the calcium level in the SR via enhancing SERCA activity by reducing the luminal H 2 O 2 -oxidized cysteines [41]. This is clearly visible in Fig.…”

Update on Selenoprotein Biosynthesis

“…Expressed during embryonic development of skeletal muscle and to a lesser extend in adult tissue, SelN is an ER glycoprotein. SelN is involved in ER redox process and calcium homeostasis (98). In addition to this severe disease, other studies associate single nucleotide polymorphisms (SNPs) in selenoprotein genes with increased risk of cancers, notably colon cancer (103,104).…”