Selective Autophagy Controls Innate Immune Response Through a Tak1/Tab2/Sh3px1 Axis

Selective autophagy is a catabolic route which turns over specific cellular material for degradation by lysosomes, and whose role in the regulation of innate immunity is largely unexplored. Here, we show that the apical kinase of the Drosophila immune deficiency (Imd) pathway Tak1, as well as its co-activator Tab2, are both novel selective autophagy substrates that interact with the autophagy protein Atg8a. We also show a role for the Atg8a-interacting protein Sh3px1 in the downregulation of the Imd pathway, by facilitating targeting of the Tak1/Tab2 complex to the autophagy platform through its interaction with Tab2. Our findings show the Tak1/Tab2/Sh3px1 interactions with Atg8a mediate the selective autophagic degradation of the Tak1/Tab2 complex, which in turn prevents constitutive activation of the Imd pathway in Drosophila. This study provides mechanistic insight on the regulation of innate immune responses by selective autophagy.