Research ArticleCell Biology

Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing

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Science Signaling  04 Dec 2018:
Vol. 11, Issue 559, eaat6903
DOI: 10.1126/scisignal.aat6903

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Cleaving a different function for p62

The scaffold protein p62 has a critical role in autophagy, the regulated degradation of proteins and organelles, and xenophagy, an autophagic process that clears invading pathogens and that may require the activation of Toll-like receptors (TLRs). Sanchez-Garrido et al. (see also the Focus by Martens) found that in skin fibroblasts, stimulation of TLR3, which detects double-stranded RNA typical of microbial pathogens, resulted in the generation by the protease caspase-8 of a proteolytic fragment of p62 that the authors called p62TRM. Instead of functioning in autophagy or xenophagy, p62TRM enhanced the ability of the amino acid leucine to activate mTORC1, a multiprotein complex that couples cellular growth and proliferation to nutrient availability. This function was lost in p62 variants with mutations in the caspase-8 cleavage site, one of which is associated with frontotemporal dementia. Thus, proteolytic cleavage of p62 generates a fragment with a distinct cellular function from that of the full-length protein, and loss of this cleavage event may account for the symptoms of patients with mutations in the gene encoding p62.