ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97

Area of Science:

• Molecular Biology
• Cellular Biology
• Neuroscience

Background:

• Autophagy and stress granule dynamics are implicated in inclusion body myopathy (IBM).
• The precise roles of core autophagy proteins in IBM and stress granule regulation are not well understood.

Purpose of the Study:

• To investigate the function of core autophagy proteins ULK1 and ULK2 in muscle.
• To elucidate the mechanisms linking autophagy, stress granules, and IBM pathogenesis.

Main Methods:

• Generated Ulk1/2-deficient mouse models.
• Analyzed muscle pathology, including vacuolar myopathy and protein inclusions.
• Investigated the interaction of ULK1/2 with VCP and stress granules using biochemical and cellular assays.

Main Results:

• Disrupted ULK1/2 expression in mice led to vacuolar myopathy with ubiquitin and TDP-43 inclusions, resembling VCP/p97 mutation-induced IBM.
• ULK1/2 localize to stress granules and phosphorylate VCP, enhancing its activity in stress granule disassembly.
• ULK1/2 deficiency resulted in impaired stress granule disassembly and contributed to IBM-like pathology.

Conclusions:

• ULK1/2 play a critical role in maintaining muscle integrity by regulating stress granule dynamics.
• VCP dysregulation and impaired stress granule disassembly are key factors in Ulk1/2-deficient mouse myopathy.
• ULK1/2 agonists represent potential therapeutic targets for IBM by enhancing stress granule disassembly.