Atg9 Interacts with dTRAF2/TRAF6 to Regulate Oxidative Stress-Induced JNK Activation and Autophagy Induction

Abstract

Autophagy is a highly conserved catabolic process that degrades and recycles intracellular components through the lysosomes. Atg9 is the only integral membrane protein among autophagy-related (Atg) proteins thought to carry the membrane source for forming autophagosomes. Here we show that Drosophila Atg9 interacts with Drosophila tumor necrosis factor receptor-associated factor 2 (dTRAF2) to regulate the c-Jun N-terminal kinase (JNK) signaling pathway. Significantly, depletion of Atg9 and dTRAF2 compromised JNK-mediated intestinal stem cell proliferation and autophagy induction upon bacterial infection and oxidative stress stimulation. In mammalian cells, mAtg9 interacts with TRAF6, the homolog of dTRAF2, and plays an essential role in regulating oxidative stress-induced JNK activation. Moreover, we found that ROS-induced autophagy acts as a negative feedback regulator of JNK activity by dissociating Atg9/mAtg9 from dTRAF2/TRAF6 in Drosophila and mammalian cells, respectively. Our findings indicate a dual role for Atg9 in the regulation of JNK signaling and autophagy under oxidative stress conditions.

Expression of Ceramide Synthase 6 Transcriptionally Activates Acid Ceramidase in a c-Jun N-terminal Kinase (JNK)-dependent Manner

“…These results are consistent with previous studies that show activation of the JNK pathway following ceramide stress as well as with ceramide/AP-1-dependent transcriptional activation of acid ceramidase following radiation therapy in prostate cancer cells (31)(32)(33)(34). JNK belongs to the larger group of mitogen-activated protein kinases and responds to a variety of signals including cytokines, radiation, heat shock, and autophagy (46,47). How CerS6 overexpression impacts on signaling pathways other than apoptosis largely remains to be determined.…”

p62/Sequestosome-1, Autophagy-related Gene 8, and Autophagy in Drosophila Are Regulated by Nuclear Factor Erythroid 2-related Factor 2 (NRF2), Independent of Transcription Factor TFEB

“…The most obvious possibility is that CncC controls autophagy in response to reactive oxygen species. Previous studies have established that Drosophila utilizes a TRAF6/Atg9/Jun N-terminal kinase (JNK) stress pathway to activate autophagy upon oxidative stress provoked by hydrogen peroxide feeding (80,81). In concordance with those studies, we found no evidence that CncC activity is required for autophagy induced upon hydrogen peroxide feeding (results not shown).…”

Drosophila Gyf/GRB10 interacting GYF protein is an autophagy regulator that controls neuron and muscle homeostasis

“…Supporting this idea, we have found that Gyf is required for Atg1-Atg13-induced Atg9 puncta formation, which reflects active membrane trafficking to autophagosomes. 31,32 In addition, although Gyf does not control Atg1-induced Atg13 phosphorylation, it was necessary for Atg1-induced Atg13 puncta formation in developing eye discs, suggesting that Gyf may control autophagy by regulating subcellular localization of the Atg1-Atg13 protein complex.…”

“…4C and D), which are known to be accumulated during active autophagy. 31,32 We tested the requirement of Gyf in this process. Silencing of Gyf strongly abrogated the Atg9 puncta formation (Fig.…”