Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response

Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response

Author Silva, Richard Cardoso da Autor UNIFESP Google Scholar
Sattlegger, Evelyn Google Scholar
Castilho, Beatriz Amaral de Autor UNIFESP Google Scholar
Abstract Genetic and pharmacological interventions in yeast and mammalian cells have suggested a cross-talk between the actin cytoskeleton and protein synthesis. Regulation of the activity of the translation initiation factor 2 (eIF2) is a paramount mechanism for cells to rapidly adjust the rate of protein synthesis and to trigger reprogramming of gene expression in response to internal and external cues. Here, we show that disruption of F-actin in mammalian cells inhibits translation in a GCN2-dependent manner, correlating with increased levels of uncharged tRNA. GCN2 activation increased phosphorylation of its substrate eIF2a and the induction of the integrated stress response master regulator, ATF4. GCN2 activation by latrunculin-B is dependent on GCN1 and inhibited by IMPACT. Our data suggest that GCN2 occurs in two different complexes, GCN2-eEF1A and GCN2-GCN1. Depolymerization of F-actin shifts GCN2 to favor the complex with GCN1, concomitant with GCN1 being released from its binding to IMPACT, which is sequestered by G-actin. These events might further contribute to GCN2 activation. Our findings indicate that GCN2 is an important sensor of the state of the actin cytoskeleton.
Keywords Translation initiation
GCN2
Actin
GCN1
EEF1A
IMPACT
xmlui.dri2xhtml.METS-1.0.item-coverage Cambridge
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Health Research Council of New Zealand Emerging Researcher grant
Auckland Medical Research Foundation
Maurice and Phyllis Paykel Trust
Massey University Research Fund
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number FAPESP: 2009/52047-5
FAPESP: 2014/23889-6
CNPq: 309860/2011-3
CNPq: 478903/2012-0CAPES: 2014/17145-4
Date 2016
Published in Journal Of Cell Science. Cambridge, v. 129, n. 24, p. 4521-4533, 2016.
ISSN 0021-9533 (Sherpa/Romeo, impact factor)
Publisher Company Of Biologists Ltd
Extent 4521-4533
Origin http://dx.doi.org/10.1242/jcs.194738
Access rights Closed access
Type Article
Web of Science ID WOS:000391103700009
URI https://repositorio.unifesp.br/handle/11600/56545

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