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

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Title: Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing
Authors: Sanchez-Garrdio, J
Sancho-Shimizu, V
Shenoy, A
Item Type: Journal Article
Publication Date: 2018-12-04
2019-02-05T09:24:05Z
Abstract: 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.
Issue Date: 4-Dec-2018
Date of Acceptance: 5-Nov-2018
URI: http://hdl.handle.net/10044/1/66236
DOI: https://dx.doi.org/10.1126/scisignal.aat6903
ISSN: 1937-9145
Publisher: American Association for the Advancement of Science
Journal / Book Title: Science Signaling
Volume: 11
Issue: 559
Copyright Statement: © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License.
Sponsor/Funder: The Royal Society
Wellcome Trust
Funder's Grant Number: RG130811
108246/Z/15/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
HERPES-SIMPLEX ENCEPHALITIS
CELL-DEATH
SELECTIVE AUTOPHAGY
VIRUS ENCEPHALITIS
TLR3 DEFICIENCY
PAGETS-DISEASE
APOPTOSIS
PROTEIN
MTORC1
METABOLISM
0601 Biochemistry And Cell Biology
Publication Status: Published
Article Number: eaat6903
Appears in Collections:Department of Medicine
Faculty of Medicine



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