Editors' ChoiceCell Biology

Atg9 Induces JNK-Mediated Stress Signaling

Sci. Signal.  17 Dec 2013:
Vol. 6, Issue 306, pp. ec309
DOI: 10.1126/scisignal.2005007

Autophagy-related (Atg) proteins have diverse functions required for autophagy. The transmembrane protein Atg9 is required for starvation-induced autophagy and is thought to mediate the transfer of lipids from endosomes and the trans-Golgi network to growing autophagosomes upon starvation. Tang et al. report that Atg9 also induces c-Jun N-terminal kinase (JNK) signaling and autophagy in response to oxidative stress. Atg9 was required for starvation-induced autophagy in the fat body of Drosophila melanogaster larvae, but overexpression of Atg9 in this tissue did not induce autophagy in nutrient-rich conditions. However, overexpression of Atg9 induced JNK-dependent apoptosis in larval imaginal discs. Genetic epistasis experiments placed Atg9 upstream of the JNK Basket, the JNK kinase Hemipterous, and the scaffold protein dTRAF2, Drosophila tumor necrosis factor receptor–associated factor 2. Atg9 and dTRAF2 coimmunoprecipitated from fly lysates. Although JNK signaling is not required for starvation-induced autophagy, it promotes autophagy and tissue renewal in response to oxidative stress. Feeding adult flies the free-radical producer paraquat or infecting them with an enterobacterium increases reactive oxygen species, JNK signaling, and stem cell proliferation in the gut; increasing JNK signaling and JNK-induced autophagy protects flies from oxidative damage and death resulting from these insults. Atg9 and dTRAF2 were required for JNK activation, autophagy induction, and stem cell proliferation in the guts of flies fed paraquat or infected with enterobacteria and reduced mortality of these animals. The authors also identified a negative feedback loop in which oxidative stress–induced autophagy reduced JNK signaling and disrupted the interaction between Atg9 and dTRAF2. In human cell lines, mammalian Atg9 interacted with TRAF6 (the human dTRAF2 homolog), Atg9 and TRAF6 were required for JNK activation in response to oxidative stress, and autophagy also appeared to negatively regulate oxidative stress–induced JNK signaling. This study thus identifies a conserved mechanism by which Atg9 interacts with dTRAF2 or TRAF6 to promote JNK signaling, perhaps by modulating the E3 ubiquitin ligase activity of these TRAFs or recruiting them to subcellular sites of oxidative stress where they can then activate JNK-mediated protective responses.

H.-W. Tang, H.-M. Liao, W.-H. Peng, H.-R. Lin, C.-H. Chen, G.-C. Chen, Atg9 interacts with dTRAF2/TRAF6 to regulate oxidative stress-induced JNK activation and autophagy induction. Dev. Cell 27, 489–503 (2013). [PubMed]