The control of other stress pathway

The control of other stress pathways by autophagy was discussed briefly in previous sections. For example, as noted above, deficient autophagy leads to p62 accumulation, which alters NF-kB signaling (Mathew et al., 2009). In addition, p62 accumulation in the setting of deficient autophagy activates the stress responsive transcription factor Nrf2 (Komatsu et al., 2010). High levels of p62 disrupt the interaction between the Cul3/Rbx1 ubiquitin ligase complex, Keap1 (which normally targets Nrf2 for proteasomal degradation), and Nrf2, resulting in enhanced Nrf2 activity and an increase in expression of Nrf2-regulated stress response enzymes (Komatsu et al., 2010) (Figure 6B). In addition, several different autophagy genes regulate different aspects of inflammatory signaling, although, in some instances, it is not known whether such regulation is a consequence of autophagy or alternative functions of the autophagy genes (Sumpter and Levine, 2010; Virgin and Levine, 2009). Autophagy genes negatively regulate RLR-mediated induction of type I interferon both via conjugation of Atg12-Atg5 to CARD domains of RLR signaling molecules and through elimination of dysfunctional mitochondria. Atg16L1 and Atg7 negatively regulate inflammatory signaling, including IL-1b and IL-18 secretion. Moreover, Atg9, but not Atg7, negatively regulates activation of STING, a recently discovered transmembrane protein that is required for efficient activation of type I IFN and proinflammatory cytokine production i in response to interferon stimulatory DNA (Saitoh et al., 2009).