LAUSR

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 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 and cells lacking SEPN1 are conspicuously defective in ER calcium re-uptake. In addition, SEPN1 is enriched at mitochondria-associated ER membranes (MAMs), which are essential for the transfer of calcium from the ER to the mitochondria and the lack of SEPN1 results in impaired mitochondrial calcium levels and metabolic homeostasis in skeletal muscle. These observations demonstrate the involvement of SEPN1 in ER redox and calcium homeostasis and suggest that the restore of redox-dependent calcium flux, may ameliorate the myopathy of SEPN1 deficiency.