Sigma-1 receptor recruits LC3 mRNA to ER-associated omegasomes to promote localized LC3 translation enabling functional autophagy
Jeffrey Knupp,
Yu-Jie Chen,
Emily Wang,
Peter Arvan,
Billy Tsai
Affiliations
Jeffrey Knupp
Department of Cell & Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, BSRB 3043, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Program, University of Michigan Medical School, 1135 Catherine Street, Ann Arbor, MI 48109 USA
Yu-Jie Chen
Department of Cell & Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, BSRB 3043, Ann Arbor, MI 48109, USA
Emily Wang
Department of Cell & Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, BSRB 3043, Ann Arbor, MI 48109, USA
Peter Arvan
Cellular and Molecular Biology Program, University of Michigan Medical School, 1135 Catherine Street, Ann Arbor, MI 48109 USA; Division of Metabolism Endocrinology & Diabetes, University of Michigan Medical School, 1000 Wall Street, Ann Arbor, MI 48105, USA; Corresponding author
Billy Tsai
Department of Cell & Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, BSRB 3043, Ann Arbor, MI 48109, USA; Cellular and Molecular Biology Program, University of Michigan Medical School, 1135 Catherine Street, Ann Arbor, MI 48109 USA; Corresponding author
Summary: Autophagosome formation initiated on the endoplasmic reticulum (ER)-associated omegasome requires LC3. Translational regulation of LC3 biosynthesis is unexplored. Here we demonstrate that LC3 mRNA is recruited to omegasomes by directly binding to the ER transmembrane Sigma-1 receptor (S1R). Cell-based and in vitro reconstitution experiments show that S1R interacts with the 3′ UTR of LC3 mRNA and ribosomes to promote LC3 translation. Strikingly, the 3′ UTR of LC3 is also required for LC3 protein lipidation, thereby linking the mRNA-3′ UTR to LC3 function. An autophagy-defective S1R mutant responsible for amyotrophic lateral sclerosis cannot bind LC3 mRNA or induce LC3 translation. We propose a model wherein S1R de-represses LC3 mRNA via its 3′ UTR at the ER, enabling LC3 biosynthesis and lipidation. Because several other LC3-related proteins use the same mechanism, our data reveal a conserved pathway for localized translation essential for autophagosome biogenesis with insights illuminating the molecular basis of a neurodegenerative disease.
