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 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, 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 VCP dysregulation and defective 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 exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.

自噬和应激颗粒动力学的紊乱被认为是包涵体肌病 (IBM) 和相关疾病的潜在机制。然而，核心自噬蛋白在 IBM 和应激颗粒动力学中的作用仍然知之甚少。在这里，我们证明小鼠中核心自噬蛋白 ULK1 和 ULK2 的表达中断会导致泛素和 TDP-43 阳性包涵体的空泡肌病；这种肌病与 VCP/p97 突变引起的肌病类似，后者是家族性 IBM 的最常见原因。从机制上讲，我们表明 ULK1/2 定位于应激颗粒并磷酸化 VCP，从而增加 VCP 的活性和分解应激颗粒的能力。这些数据表明，VCP 失调和应激颗粒分解缺陷导致Ulk1/2缺陷小鼠出现 IBM 样疾病。此外，ULK1/2 激动剂可加速应激颗粒的分解，表明 ULK1/2 是利用应激颗粒的高阶调节来治疗 IBM 及相关疾病的靶标。