Universität zu Köln

Tawo, Riga, Pokrzywa, Wojciech ORCID: 0000-0002-5110-4462, Kevei, Eva ORCID: 0000-0002-0560-9208, Akyuz, Melek E., Balaji, Vishnu, Adrian, Svenja, Hoehfeld, Joerg and Hoppe, Thorsten ORCID: 0000-0002-4734-9352 (2017). The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover. Cell, 169 (3). S. 470 - 496. CAMBRIDGE: CELL PRESS. ISSN 1097-4172

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Abstract

Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tawo, Riga UNSPECIFIED UNSPECIFIED UNSPECIFIED Pokrzywa, Wojciech UNSPECIFIED orcid.org/0000-0002-5110-4462 UNSPECIFIED Kevei, Eva UNSPECIFIED orcid.org/0000-0002-0560-9208 UNSPECIFIED Akyuz, Melek E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Balaji, Vishnu UNSPECIFIED UNSPECIFIED UNSPECIFIED Adrian, Svenja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehfeld, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Thorsten UNSPECIFIED orcid.org/0000-0002-4734-9352 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-233828
DOI:	10.1016/j.cell.2017.04.003
Journal or Publication Title:	Cell
Volume:	169
Number:	3
Page Range:	S. 470 - 496
Date:	2017
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1097-4172
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-QUALITY CONTROL; CAENORHABDITIS-ELEGANS DAF-2; C-ELEGANS; MOLECULAR CHAPERONES; TRANSCRIPTION FACTOR; SIGNALING PATHWAY; TRIAGE DECISIONS; E3 LIGASE; LIFE-SPAN; LONGEVITY Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23382