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.


The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget’s disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM. We found that p62TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1). The kinase RIPK1 and caspase-8 controlled p62TRM production and thus promoted mTORC1 signaling. An FTD-linked p62 D329G polymorphism and a rare D329H variant could not be proteolyzed by caspase-8, and these noncleavable variants failed to activate mTORC1, thereby revealing the detrimental effect of these mutations. These findings on the role of p62TRM provide new insights into SQSTM1-linked diseases and mTORC1 signaling.

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