deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast破译人类热休克转录因子1通过翻译后修饰调控酵母.pdf

Deciphering Human Heat Shock Transcription Factor 1 Regulation via Post-Translational Modification in Yeast 1. 2. 3 1 Liliana Batista-Nascimento , Daniel W. Neef , Phillip C. C. Liu , Claudina Rodrigues-Pousada , Dennis J. Thiele2* ´ ´ 1 Genomics and Stress Laboratory, Instituto de Tecnologia Quımica e Biologica, Oeiras, Portugal, 2 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, United States of America, 3 Applied Technology Group, Incyte Corporation, Wilmington, Delaware, United States of America Abstract Heat shock transcription factor 1 (HSF1) plays an important role in the cellular response to proteotoxic stresses. Under normal growth conditions HSF1 is repressed as an inactive monomer in part through post-translation modifications that include protein acetylation, sumoylation and phosphorylation. Upon exposure to stress HSF1 homotrimerizes, accumulates in nucleus, binds DNA, becomes hyper-phosphorylated and activates the expression of stress response genes. While HSF1 and the mechanisms that regulate its activity have been studied for over two decades, our understanding of HSF1 regulation remains incomplete. As previous studies have shown that HSF1 and the heat shock response promoter element (HSE) are generally structurally conserved from yeast to metazoans, we have made use of the genetically tractable budding yeast as a facile assay system to further understand the mechanisms that regulate human HSF1 through phosphorylation of serine 303. We show that when human HSF1 is expressed in yeast its phosphorylation at S303 is promoted by the MAP- kinase Slt2 in