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@article{Sanchez-Garrdio:2018:10.1126/scisignal.aat6903,
author = {Sanchez-Garrdio, J and Sancho-Shimizu, V and Shenoy, A},
doi = {10.1126/scisignal.aat6903},
journal = {Science Signaling},
title = {Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing},
url = {http://dx.doi.org/10.1126/scisignal.aat6903},
volume = {11},
year = {2018}
}
TY - JOUR
AB - 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.
AU - Sanchez-Garrdio,J
AU - Sancho-Shimizu,V
AU - Shenoy,A
DO - 10.1126/scisignal.aat6903
PY - 2018///
SN - 1937-9145
TI - Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing
T2 - Science Signaling
UR - http://dx.doi.org/10.1126/scisignal.aat6903
UR - http://hdl.handle.net/10044/1/66236
VL - 11
ER -
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