Turning off cellular stress

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Science Signaling  14 May 2019:
Vol. 12, Issue 581, eaax9738
DOI: 10.1126/scisignal.aax9738

Independently of autophagy, the kinases ULK1/2 promote stress granule disassembly and prevent the development of skeletal muscle disease.

Cellular stress promotes the assembly of membrane-less structures associated with impaired mRNA translation, which are known as stress granules. The assembly of stress granules is associated with degenerative disorders of the muscle, bone, and the nervous system that are also linked to mutations in autophagy proteins. Wang et al. found that hypomorphic expression in mice of the serine/threonine unc-51–like autophagy-activating kinase 1 (ULK1) and ULK2 resulted in a disease similar to inclusion body myopathy (IBM), a progressive skeletal muscle disorder that makes walking increasingly difficult. In comparison with WT mice, Ulk1–/–Ulk2+/– mice had decreased grip strength, disrupted normal myofiber architecture, and aberrant subcellular localization of the RNA binding proteins TDP-43 and TIA-1 in muscle cells. These effects were less apparent in mice lacking the ubiquitin-like modifier activating enzyme ATG7, which is essential for autophagosome formation. Instead, immunoproteomics identified that ULK1 likely interacted with several proteins normally associated with stress granules, and immunofluorescence microscopy showed that endogenous ULK1/2 were recruited to TIA-1+ stress granules in mouse embryonic fibroblasts and myoblast-like C2C12 cells after heat shock. Pharmacological inhibition of ULK1/2 activity and knockdown of ULK1/2 prolonged the appearance of heat shock– or sodium arsenite–induced stress granules. Conversely, a ULK1/2 agonist promoted stress granule disassembly in human U20S and HeLa cell lines. In addition to stress granules proteins, ULK1 interacted with the ATPase VCP and promoted its phosphorylation at Ser13, Ser282, and Thr761. Substitution of these residues in VCP with alanines inhibited heat shock–induced stress granule resolution. In contrast, substitution of the same residues with phospho-mimetic aspartates augmented ATPase activity and stress granule disassembly, even when ULK1 abundance was reduced. Together, these data suggest that ULK1/2 stimulates stress granule disassembly by activating the ATPase VCP. Because of the difficulty of directly targeting this essential ATPase, these data imply that stimulating its activation through ULK1/2 may be beneficial in myopathy and potentially other diseases associated with aberrant stress granule assembly.

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