SIGMAR1/Sigma-1 receptor: a key regulator in stabilizing and translating <i>LC3B</i> mRNA for autophagosome formation

Macroautophagy/autophagy degrades and recycles cellular constituents via the lysosome to maintain cellular homeostasis. Our study identified the endoplasmic reticulum (ER)-resident SIGMAR1 (sigma non-opioid intracellular receptor 1) as a critical regulator of the biosynthesis of Atg8-family proteins that leads to the lipidation that is essential during autophagosome formation. We demonstrate that SIGMAR1 stabilizes <i>MAP1LC3B/LC3B</i> and <i>GABARAP</i> mRNAs, promoting their localized translation proximal to the ER for efficient lipidation. Using single-molecule fluorescence <i>in situ</i> hybridization/smFISH and co-immunoprecipitation, we found that SIGMAR1 directly binds to a conserved region in the 3' UTR of <i>LC3B</i> mRNA, facilitating its translation, efficient lipidation, and proper integration into the phagophore membrane. Cells lacking SIGMAR1 show reduced levels of many Atg8-family proteins and impaired autophagic flux. Our model suggests that SIGMAR1-mediated localized translation of Atg8-family proteins at the ER promotes efficient autophagosome formation, in contrast to recruiting preexisting cytosolic Atg8-family proteins to the lipidation machinery. Elucidating the role of SIGMAR1 in autophagy may provide better therapeutic strategies to prevent or treat autophagy-dependent neurodegenerative diseases, particularly given the highly druggable nature of SIGMAR1.