…
comment: The repository administrator has not yet configured an RDF license.
primary topic: HSc70 interactome reveal major role of macroautophagy and minor role of chaperone mediated autophagy in K-Ras G12V cell proliferation and survival

HSc70 interactome reveal major role of macroautophagy and minor role of chaperone mediated autophagy in K-Ras G12V cell proliferation and survival
type: AcademicArticle
type: Article
abstract: Constitutively active K-Ras oncogene mutation at G12V changes the proteome of cells and activates macroautophagy for cell advantage. Inhibition of macroautophagy impairs K-Ras mediated tumor progression to a limited extent with increase of spontaneous tumors due to poorly understood mechanisms. Here, we show that inhibition of macroautophagy in K-Ras G12V mouse embryonic fibroblasts (MEFs) hyper activates chaperon mediated autophagy (CMA). Quantitative identification of CMA substrates through co-immunoprecipitation of CMA component heat shock cognate 70 (Hsc70) demonstrates a shift of proteins from macroautophagy to CMA mediated degradation. However, macroautophagy impairment show significant inhibition on proliferation and CMA hyper activation provides a basal support to macroautophagy-inhibited MEFs for survival. On the other hand, K-Ras G12V MEFs impaired of CMA reduces number of Hsc70 clients but activated macroautophagy significantly compensated CMA loss. Nonetheless, co-inhibition of CMA and macroautophagy had a synergistic detrimental effect on both proliferation and survival of MEFs expressing K-Ras G12V mutant. Our results point to K-Ras G12V MEFs dependency on macroautophagy and CMA partly compensates its loss for survival but not hyper-proliferation; implicating that targeting both macroautophagy and CMA as a promising therapeutic target in G12V mutation associated K-Ras cancers. SIGNIFICANCE: The present study provides a framework of Hsc70 interacting proteins, which differentially interact with Hsc70 in response to autophagy alterations. The role of proteins accumulation and induced proteo-toxicity could be underlying factor in macroautophagy and CMA co-inhibited K-Ras G12V MEFs phenotype. Our study provides rational for adaptive mechanisms in K-Ras tumors inhibited with different autophagy pathways and also supports targeting both macroautophagy and CMA simultaneously as therapeutic target. At the same time current study will help in characterizing the…
date: 2022-07-30
volume: 264
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

Elsevier
type: Organization

JOURNAL OF PROTEOMICS
type: Collection

Amit Kumar
type: Person
given name: Amit
family name: Kumar

Vipin Kumar Yadav
type: Person
given name: Vipin Kumar
family name: Yadav

Rachna Behl
type: Person
given name: Rachna
family name: Behl

Poorwa Awasthi
type: Person
given name: Poorwa
family name: Awasthi

HTML Summary of #3058 HSc70 interactome reveal major role of macroautophagy and minor role of chaperone mediated autophagy in K-Ras G12V cell proliferation and survival
format: text/html
primary topic: HSc70 interactome reveal major role of macroautophagy and minor role of chaperone mediated autophagy in K-Ras G12V cell proliferation and survival

QR Microbiology
type: Concept