A two‐hybrid screen identifies an unconventional role for the intermediate filament peripherin in regulating the subcellular distribution of the SNAP25‐interacting protein,SIP30

Peripherin is a type III intermediate filament protein, the expression of which is associated with the acquisition and maintenance of a terminally differentiated neuronal phenotype. Peripherin up‐regulation occurs during acute neuronal injury and in degenerating motor neurons of amyotrophic lateral sclerosis. The functional role(s) of peripherin during normal, injurious, and disease conditions remains unknown, but may be related to differential expression of spliced isoforms. To better understand peripherin function, we performed a yeast two‐hybrid screen on a mouse brain cDNA library using an assembly incompetent peripherin isoform, Per‐61, as bait. We identified new peripherin interactors with roles in vesicular trafficking, signal transduction, DNA/RNA processing, protein folding, and mitochondrial metabolism. We focused on the interaction of Per‐61 and the constitutive isoform, Per‐58, with SNAP25 interacting protein 30 (SIP30), a neuronal protein involved in SNAP receptor‐dependent exocytosis. We found that peripherin and SIP30 interacted through coiled‐coil domains and colocalized in cytoplasmic aggregates in SW13vim(?) cells. Interestingly, Per‐61 and Per‐58 differentially altered the subcellular distribution of SIP30 and SNAP25 in primary motor neurons. Our findings suggest a novel role of peripherin in vesicle trafficking.