| Organisms commonly encounter oxidative stress originating from endogenous sources or in the form of exogenous stressors. Oxidative stress has been implicated in the pathogenesis of various diseases and aging. Thus, boosting the resistance against oxidative stress might be a strategy to delay or prevent the onset of diseases, promote organismal survival, and slow down aging. Recent findings have implicated autophagy, a conserved catabolic process, into the cellular defense against various biological and xenobiotic stresses including oxidative stress. However, the regulation of autophagy in response to oxidative stress remains largely elusive. One central regulatory system of the organism's defense against oxidative stress is the JNK pathway. It has been shown previously that JNK gain-of-function mutants are more resistant to acute stress exposure. Furthermore, the JNK pathway has been reported to affect the lifespan of metazoans, presumably be deflecting oxidative damage. The downstream effectors of JNK in this context are not completely understood. In this thesis, I studied the regulation of autophagy by JNK signaling upon oxidative stress exposure, using the Drosophila melanogaster midgut as model organ. I found that the mRNA levels of key aut ophagy-related (ATG) genes, ATG1, ATG8a, and ATG18.2, are upregulated in oxidatively stressed animals. This activation correlates well with JNK activation after oxidative challenge. Interestingly, JNK signaling is sufficient both to activate the transcription of multiple ATG genes, and to induce prominent autophagy in midgut cells. Furthermore, oxidative stress stimulates autophagy in a JNK-dependent manner in Drosophila midgut. Consistently, loss-of-function mutations in ATG genes could abrogate the stress resistance phenotype in JNK gain-of-function mutants. In line with the idea that JNK mediated transcriptional activation of ATG gene activity might promote stress resistance, enhancing autophagy by overexpressing ATG6 is sufficient to improve the survival of Drosophila upon oxidative stress. Thus, autophagy emerges as an integral part of JNK-mediated oxidative defense.;Autophagy is a pleiotropic process. In addition to its regulation by oxidative stress, it can be regulated by developmental cues like ecdysone and by nutritional deprivation. We examined whether the role of JNK in autophagy extends to starvation and ecdysone responses. In contrast to its essential function for autophagy elicited by oxidative stress, JNK is dispensable for the induction of autophagy in these two biological situations. These results suggest that autophagy can be regulated in a context-dependent manner by different signaling pathways.;Taken together, my findings provide new insights into the molecular mechanisms by which JNK signaling protects Drosophila from oxidative insults, and might provide a starting point for investigating the potential function of the JNK-autophagy axis in physiology and disease of higher organisms as well. |
