Efeitos do fármaco salicilato de sódio sobre o ramo da via de resposta a proteínas mal dobradas mediado pelo fator de transcrição ATF6α

• Ano de defesa: 2018
• Autor(a) principal: Fernanda Lins Brandão Mügge
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; ICB - INSTITUTO DE CIÊNCIAS BIOLOGICAS; Programa de Pós-Graduação em Biologia Celular; UFMG
• Palavras-chave em Português: Biologia Celular; Estresse do Retículo Endoplasmático; Fator 6 Ativador da Transcrição; Salicilato de Sódio
• Link de acesso: http://hdl.handle.net/1843/33887

The endoplasmic reticulum (ER) is a cellular organelle responsible for the synthesis and post-translational modifications of many cellular and secreted proteins. Perturbation of the homeostasis of the ER by the accumulation of unfolded proteins triggers the ER stress response, which is mediated by three ER transmembrane proteins: PERK, ATF6 e IRE1. The activation of this response leads the cell to shut down the global mRNA translation and start a gene transcriptional activation program that will increase the capacity of the cell to fold or degrade the unfolded proteins. PERK and IRE1 are activated by oligomerization and phosphorylation, while ATF6 activation occurs after being transported from ER to Golgi apparatus where it is cleaved by the proteases S1P and S2P to form an active transcription factor that will eventually be translocated to the cell nucleus. Accumulating evidence indicate that anti-inflammatory drugs salicylates, like aspirin and sodium salicylate (NaSal), can activate PERK, but not IRE1. Because the role of ATF6 in the cellular responses induced by salicylates remained elusive, we aimed to characterize the expression and activity of ATF6 after NaSal treatment of cells. Expression of ATF6 was determined through RT-qPCR and western blot and its activation was evaluated by luciferase gene reporter, fluorescence microscopy and flow cytometry studies. We found that NaSal treatment of cells leads to increases in ATF6α mRNA and protein levels; however, these events are not accompanied by ATF6 activation. Conversely, NaSal inhibited ATF6 transactivating activity elicited by various ER stress-inducing agents in different cell types. Mechanistically, exposure of cells to NaSal results in ATF6α trapping at the Golgi apparatus, thus preventing nuclear translocation. This resulted in the inhibition of the expression of a subset of ATF6α target genes. This study describes ATF6 as a newly molecular target for the biological actions of sodium salicylate, by restraining its activity, and thereby preventing the activation of a specific subset of ER-stress responsive genes.