ULK1/2 Regulates Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97

Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet, the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1/2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43-positive inclusions, similar to that caused by mutations in VCP, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that dysregulation of VCP and stress granule disassembly contribute to IBM-like disease in Ulk1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for leveraging higher-order regulation of stress granules for therapeutic intervention in IBM and related disorders.