title: Tunicamycin-induced ER stress upregulates the expression of mitochondrial HtrA2 and promotes apoptosis through the cytosolic release of HtrA2.
abstract: Recent studies provide some evidence that the HtrA2 protein is intimately associated with the pathogenesis of neurodegenerative disorders and that endoplasmic reticulum (ER) quality control and ER stress-associated cell death play critical roles in neuronal cell death. However, little is known about the intimate relationship between HtrA2 and ER stress-associated cellular responses. In the present study, we have demonstrated that the HtrA2 protein level was gradually and significantly increased by up to 10-fold in the mitochondria under tunicamycin (Tm)-induced ER stress, which eventually promoted cell death through the release of HtrA2 into the cytoplasm. Using an ecdysone-inducible mammalian expression system, we demonstrate that the extent of cell death in 293-HtrA2 cells was approximately 20 times higher under Tm-induced ER stress, indicating that the increase in the HtrA2 protein level in the mitochondria itself is necessary but not sufficient for the promotion of cell death. Taken together, these results suggest that HtrA2 may serve as a mediator of ER stress-induced apoptosis and ER-mitochondrial cross-talk in some cellular processes.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Chul
authors.initials: C
authors.lastname: Han
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Nam
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Young-Mo
authors.initials: YM
authors.lastname: Seong
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
authors.forename: Hangshuk
authors.initials: H
authors.lastname: Rhim
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D005786:Gene Expression Regulation; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D012697:Serine Endopeptidases / Q000096:biosynthesis*; D013312:Stress, Physiological / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D024101:Mitochondrial Proteins; D014415:Tunicamycin; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2