title: IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans.
abstract: 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.
  
  
  
  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.
  
  
  
  IMPACT inhibits the ISR pathway, thus limiting the activation of stress response factors that are beneficial during aging and required under DR.
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Rafael C
authors.initials: RC
authors.lastname: Ferraz
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.|Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Henrique
authors.initials: H
authors.lastname: Camara
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.|Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Evandro A
authors.initials: EA
authors.lastname: De-Souza
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.|Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Silas
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.|Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Ana Paula F
authors.initials: AP
authors.lastname: Pinca
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Silva
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Vitor N
authors.initials: VN
authors.lastname: Sato
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Beatriz A
authors.initials: BA
authors.lastname: Castilho
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. morima@unicamp.br.|Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil. morima@unicamp.br.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C073702:skn-1 protein, C elegans; D011494:Protein Kinases; C578467:gcn-2 protein, C elegans
keywords: Aging; Dietary restriction; GCN2; IMPACT; Integrated stress response