title: Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response.
abstract: The ubiquitin-proteasome system represents the major pathway of selective intracellular protein degradation in eukaryotes. Misfolded proteins represent an important class of substrates for this pathway, and the failure to destroy misfolded proteins is associated with a number of human diseases. The transcription factor Rpn4 mediates a key proteotoxic stress response whose best known function is to control proteasome abundance by a homeostatic feedback mechanism. Here we identify the uncharacterized zinc finger protein Tmc1 as a dynamically regulated stress-responsive protein. Rpn4 induces TMC1 transcription in response to misfolded proteins. However, this response is counteracted by rapid proteasome-dependent degradation of Tmc1, which serves to normalize Tmc1 protein levels after induction. Precise control of Tmc1 levels is needed in vivo to survive multiple stressors related to proteostasis. Thus, Tmc1 represents a novel effector and substrate of the Rpn4 proteotoxic stress response.
authors.affiliation: From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Angel
authors.initials: A
authors.lastname: Guerra-Moreno
authors.affiliation: From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 jwhanna@partners.org.
authors.forename: John
authors.initials: J
authors.lastname: Hanna
mesh_terms: D001151:Arsenic / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000502:physiology*; D006706:Homeostasis; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C119430:RPN4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D001151:Arsenic
keywords: Rpn4; Tmc1; arsenite; proteasome; protein degradation; proteostasis; stress response; yeast