Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP

Among its various functions, the sigma-1 receptor (σ1R) has been reported to modulate macroautophagy. It is currently unknown how this activity is mediated. We phylogenetically, structurally, and biochemically analyzed σ1R regarding its function in autophagy. We identified several putative LC3-interacting-regions (LIRs) that may mediate interactions with ATG8 proteins, which are known to promote autophagosome biogenesis, autophagic cargo reception, and lysosome fusion. Human σ1R comprises a LIR motif (hLIR5) typical for interaction with a specific ATG8, GABARAP. Biochemically, we uncovered a GABARAP-σ1R interaction depending on this motif via peptide array analysis and confirmed this via immunoprecipitation, co-localization, and proximity ligation assays. In addition, we verified a LIR-dependent presence of σ1R in isolated native autophagic vesicles. Excitingly, two point mutations within this LIR that have previously been reported to be associated with autosomal-recessive distal spinal muscular atrophy lack the ability to interact with GABARAP, highlighting the physiological relevance of the hLIR5-mediated σ1R-GABARAP interaction.