Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression
Hiroki Matsumoto,
Shuichi Miyazaki,
Satoshi Matsuyama,
Masayuki Takeda,
Makoto Kawano,
Hiroshi Nakagawa,
Kazuhiko Nishimura,
Saburo Matsuo
Affiliations
Hiroki Matsumoto
Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-58, Rinku-Ourai-Kita, Izumisano 598-8531, Japan
Shuichi Miyazaki
The Center for Advanced Research, Graduate School of Medical Science, Toho University of Medicine, Ota-ku, Omori-Nishi, 5-21-16, Tokyo 143-8540, Japan
Satoshi Matsuyama
Laboratory of Veterinary Radiology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-58, Rinku-Ourai-Kita, Izumisano 598-8531, Japan
Masayuki Takeda
Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-58, Rinku-Ourai-Kita, Izumisano 598-8531, Japan
Makoto Kawano
Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-58, Rinku-Ourai-Kita, Izumisano 598-8531, Japan
Hiroshi Nakagawa
Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-58, Rinku-Ourai-Kita, Izumisano 598-8531, Japan
Kazuhiko Nishimura
Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-58, Rinku-Ourai-Kita, Izumisano 598-8531, Japan
Saburo Matsuo
Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-58, Rinku-Ourai-Kita, Izumisano 598-8531, Japan
Summary Cells exposed to ER-stress undergo the Unfolded Protein Response (UPR) to avoid apoptosis, but may also activate autophagy. However, the signal for selection of one of these two protective responses is unknown. To clarify the key switch between autophagy and apoptosis, we examined the correlation of UPR-related signals with autophagy and/or apoptosis inductions in HepG2 cells exposed to three ER-stress inducers (NaF, tunicamycin, and thapsigargin) with time, including the effect of small interfering RNA on the cell responses. Thapsigargin-induced ER-stress caused only apoptosis after ∼2 hr with Ire1 phosphorylation, and Grp78, ATF4, and CHOP expressions. On the other hand, NaF- and tunicamycin-induced ER-stress caused only autophagy in the early stage by ∼8 hr with ATF4 expression and without CHOP expression. ATF4-siRNA completely inhibited the autophagy induced by NaF or tunicamycin with suppressed ATF4 protein and mRNA expressions, and also inhibited apoptosis by thapsigargin with suppression of both ATF4 and CHOP. CHOP-siRNA had no effect on autophagy activation by NaF and tunicamycin. On the other hand, CHOP-siRNA activated autophagy in thapsigargin-induced ER-stress with significant ATF4 expression, and suppressed apoptosis with CHOP suppression. These results showed that ATF4 is the key signal for autophagy induced by ER-stress, and that autophagy is switched to apoptosis by subsequent CHOP upregulation, suggesting that the changeover switch between autophagy and apoptosis is located between ATF4 to CHOP in the PERK pathway.
