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

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• The sigma-1 receptor (σ1R) is known to modulate macroautophagy.
• The precise mechanism of σ1R's involvement in autophagy remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which σ1R modulates macroautophagy.
• To identify and characterize the interaction between σ1R and autophagy-related proteins.

Main Methods:

• Phylogenetic, structural, and biochemical analyses of σ1R.
• Identification of LC3-interacting regions (LIRs) in σ1R.
• Peptide array analysis, immunoprecipitation, co-localization, and proximity ligation assays to confirm interactions.
• Analysis of σ1R in isolated autophagic vesicles.

Main Results:

• Several putative LIRs were identified in σ1R, suggesting interaction with ATG8 proteins.
• A specific LIR motif (hLIR5) in human σ1R mediates interaction with GABARAP.
• Biochemical assays confirmed the GABARAP-σ1R interaction dependent on hLIR5.
• Mutations in the hLIR5 motif, previously linked to spinal muscular atrophy, abolished GABARAP interaction.

Conclusions:

• The GABARAP-σ1R interaction, mediated by the hLIR5 motif, is crucial for σ1R's function in autophagy.
• This interaction is physiologically relevant and its disruption is implicated in autosomal-recessive distal spinal muscular atrophy.