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Translational regulation mediated by elF2 in eukaryotes

Abstract

Translational control mediated by the phosphorylation of eukaryotic initiation factor -2 (eIF2) is important for cellular adaptation to a variety of environmental stress situtations, and its impairment results in pathological conditions in humans. One elF2 kinase, GCN2, extensively studied in the yeast model, has recently been the focus of major findings in mammalian physiology. GCN2 controls protein synthesis and the induction of a complex gene regulatory network in response to e.g., amino acid starvation. The study of mice devoid of GCN2 revealed that this protein kinase plays a role managing starvation for nutrients and determining feeding behavior and memory. Our previous work showed that the mammalian protein IMPACT is an inhibitor of GCN2. IMPACT binds to GCN1, an effectors of GCN2. Interestingly, IMPACT is predominantly expressed in neurons. This project addresses the mechanisms by which IMPACT and GCN1 modulate GCN2 activity in neurons and explores the consequences of the lack of IMPACT in mammalian physiology. Other potential functions of IMPACT and GCN1 will be addressed. The elF2 signaling pathway also directs differentiation processes in pathogenic organisms. We have previously shown that trypanosomatids contain an unusual form of elF2, and three elF2 kinases that may function as sensors of the different environmental conditions encountered by the parasites during their life cycle. This project will also dissect the role of the elF2 signaling pathway in trypanosomes. Together, the project aims are important for understanding the molecular mechanisms evolved by eukaryotic organisms to adapt a highly conserved translational regulatory module to maintain homeostasis or to promote differentiation. (AU)

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VEICULO: TITULO (DATA)

Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CASTILHO, BEATRIZ A.; SHANMUGAM, RENUKA; SILVA, RICHARD C.; RAMESH, RASHMI; HIMME, BENJAMIN M.; SATTLEGGER, EVELYN. Keeping the eIF2 alpha kinase Gcn2 in check. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1843, n. 9, p. 1948-1968, . (09/52047-5)
PEREIRA, CATIA M.; FILEV, RENATO; DUBIELA, FRANCISCO P.; BRANDAO, BRUNA B.; QUEIROZ, CLAUDIO M.; LUDWIG, RAISSA G.; HIPOLIDE, DEBORA; LONGO, BEATRIZ M.; MELLO, LUIZ E.; MORI, MARCELO A.; et al. The GCN2 inhibitor IMPACT contributes to diet-induced obesity and body temperature control. PLoS One, v. 14, n. 6, . (09/52047-5, 12/04079-8)
AVILA, CARLA CRISTI D. C.; PEACOCK, LORI; MACHADO, FABRICIO CASTRO; GIBSON, WENDY; SCHENKMAN, SERGIO; CARRINGTON, MARK; CASTILHO, BEATRIZ A.. Phosphorylation of eIF2 alpha on Threonine 169 is not required for Trypanosoma brucei cell cycle arrest during differentiation. Molecular and Biochemical Parasitology, v. 205, n. 1-2, p. 16-21, . (09/52047-5, 11/51973-3)
SILVA, RICHARD C.; DAUTEL, MARTINA; DI GENOVA, BRUNO M.; AMBERG, DAVID C.; CASTILHO, BEATRIZ A.; SATTLEGGER, EVELYN. The Gcn2 Regulator Yih1 Interacts with the Cyclin Dependent Kinase Cdc28 and Promotes Cell Cycle Progression through G2/M in Budding Yeast. PLoS One, v. 10, n. 7, . (09/52047-5)
SILVA, RICHARD C.; SATTLEGGER, EVELYN; CASTILHO, BEATRIZ A.. Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response. Journal of Cell Science, v. 129, n. 24, p. 4521-4533, . (14/17145-4, 14/23889-6, 09/52047-5)
CRISAFULLI, UMBERTO; XAVIER, ANDRE M.; DOS SANTOS, FABIANA B.; CAMBIAGHI, TAVANE D.; CHANG, SEO Y.; PORCIONATTO, MARIMELIA; CASTILHO, BEATRIZ A.; MALNIC, BETTINA; GLEZER, ISAIAS. Topical Dexamethasone Administration Impairs Protein Synthesis and Neuronal Regeneration in the Olfactory Epithelium. FRONTIERS IN MOLECULAR NEUROSCIENCE, v. 11, . (09/04437-9, 07/53732-8, 16/24471-0, 11/13134-0, 09/52047-5, 13/07937-8)
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.. IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans. BMC Biology, v. 14, . (10/52557-0, 15/01316-7, 12/24490-4, 14/25270-3, 14/10814-8, 14/17145-4, 09/52047-5, 15/04264-8, 12/04064-0, 14/25068-0)
AUGUSTO, LEONARDO DA SILVA; MORETTI, NILMAR SILVIO; PRATA RAMOS, THIAGO CESAR; LEANDRO DE JESUS, TERESA CRISTINA; ZHANG, MIN; CASTILHO, BEATRIZ A.; SCHENKMAN, SERGIO. A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi. PLOS PATHOGENS, v. 11, n. 2, . (12/50399-4, 09/52047-5, 11/51973-3)

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