title: Mitochondrial TRAP1 regulates the unfolded protein response in the endoplasmic reticulum.
abstract: Stress in mitochondria or the endoplasmic reticulum (ER) independently causes cell death. Recently, it was reported that ER stress causes mitochondrial dysfunction via p53-upregulated modulator of apoptosis (PUMA). However, little is known regarding the mitochondria molecules that mediate ER dysfunction. The present study revealed that tumor necrosis factor receptor-associated protein 1 (TRAP1), which localizes in the mitochondria, is associated with the unfolded protein response (UPR) in the ER. TRAP1 knockdown activated the ER-resident caspase-4, which is activated by ER stress, to induce cell death in humans. However, TRAP1 knockdown cells did not show a significant increase in the level of cell death at least within 24 h after early phase of ER stress in comparison with that of the control cells. This finding could be attributed to a number of reasons. TRAP1 knockdown failed to activate caspase-9, which is activated by activated caspase-4. In addition, TRAP1 knockdown increased the basal level of GRP78/BiP expression, which protects cells, and decreased the basal level of C/EBP homologous protein (CHOP) expression, which induces cell death, even under ER stress. Thus, the present study revealed that mitochondria could be a potential regulator of the UPR in the ER through mitochondrial TRAP1.
authors.affiliation: Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Takemoto
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyata
authors.forename: Hironori
authors.initials: H
authors.lastname: Takamura
authors.forename: Taiichi
authors.initials: T
authors.lastname: Katayama
authors.forename: Masaya
authors.initials: M
authors.lastname: Tohyama
mesh_terms: D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D024101:Mitochondrial Proteins / Q000502:physiology*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D024101:Mitochondrial Proteins; C092306:TRAP1 protein, human