Tunicamycin-induced ER stress upregulates the expression of mitochondrial HtrA2 and promotes apoptosis through the cytosolic release of HtrA2.
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.
Han
Chul
C
School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Nam
Min-Kyung
MK
Park
Hyo-Jin
HJ
Seong
Young-Mo
YM
Kang
Seongman
S
Rhim
Hangshuk
H
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
D024101:Mitochondrial Proteins; D014415:Tunicamycin; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2