IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans

Author(s)

Ferraz, Rafael C. ; Camara, Henrique ; De-Souza, Evandro A. ; Pinto, Silas ; Pinca, Ana Paula F. ; Silva, Richard C. ; Sato, Vitor N. ; Castilho, Beatriz A. ; Mori, Marcelo A.

• Document type: Journal article
• Source: BMC Biology; v. 14, OCT 7 2016.
• Web of Science Citations: 6

Abstract

Background: The General Control Nonderepressible 2 (GCN2) kinase is a conserved member of the integrated stress response (ISR) pathway that represses protein translation and helps cells to adapt to conditions of nutrient shortage. As such, GCN2 is required for longevity and stress resistance induced by dietary restriction (DR). IMPACT is an ancient protein that inhibits GCN2. Results: Here, we tested whether IMPACT down-regulation mimics the effects of DR in C. elegans. Knockdown of the C. elegans IMPACT homolog impt-1 activated the ISR pathway and increased lifespan and stress resistance of worms in a gcn-2-dependent manner. Impt-1 knockdown exacerbated DR-induced longevity and required several DR-activated transcription factors to extend lifespan, among them SKN-1 and DAF-16, which were induced during larval development and adulthood, respectively, in response to impt-1 RNAi. Conclusions: IMPACT inhibits the ISR pathway, thus limiting the activation of stress response factors that are beneficial during aging and required under DR. (AU)

• FAPESP's process: 10/52557-0 - Identification of mechanisms responsible for beneficial effects of calorie restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 15/01316-7 - Dicer, miRNAs and the control of mitochondrial function in the context of aging and caloric restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/24490-4 - Study of the involvement of impact in the effects of caloric restriction in C. elegans
• Grantee: Rafael Ferraz Bannitz
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/25270-3 - Study of Dicer effects on mitochondrial function, metabolism and aging in nematodes C. elegans
• Grantee: Silas Pinto da Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/10814-8 - Determination of factors that controls Dicer expression in vivo in C. elegans
• Grantee: Evandro Araújo de Souza
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/17145-4 - Translational regulation mediated by GCN2: modulation by the actin cytoskeleton
• Grantee: Richard Cardoso da Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 09/52047-5 - Translational regulation mediated by elF2 in eukaryotes
• Grantee: Beatriz Amaral de Castilho
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/04264-8 - Phenotypic screen of nematodes C. elegans mutants for proteins necessary to systemic RNAi
• Grantee: Henrique Camara
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 12/04064-0 - Search for a pharmacological intervention to mimic the beneficial effects of caloric restriction in C. elegans
• Grantee: Vitor Neves Sato
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 14/25068-0 - Unraveling new mechanisms responsible for the cell non-autonomous control of proteostasis in C. elegans
• Grantee: Ana Paula Forti Pinca
• Support Opportunities: Scholarships in Brazil - Master