Kenny mediates selective autophagic degradation of the IKK complex to control innate immune responses

Radu Tusco,Ashish Jain,Ioannis P Nezis,Anne-Claire Jacomin,Terje Johansen,Kenneth Bowitz Larsen,Bridget S Penman

doi:10.1038/s41467-017-01287-9

Abstract

Selective autophagy is a catabolic process with which cellular material is specifically targeted for degradation by lysosomes. The function of selective autophagic degradation of self-components in the regulation of innate immunity is still unclear. Here we show that Drosophila Kenny, the homolog of mammalian IKKγ, is a selective autophagy receptor that mediates the degradation of the IκB kinase complex. Selective autophagic degradation of the IκB kinase complex prevents constitutive activation of the immune deficiency pathway in response to commensal microbiota. We show that autophagy-deficient flies have a systemic innate immune response that promotes a hyperplasia phenotype in the midgut. Remarkably, human IKKγ does not interact with mammalian Atg8-family proteins. Using a mathematical model, we suggest mechanisms by which pathogen selection might have driven the loss of LIR motif functionality during evolution. Our results suggest that there may have been an autophagy-related switch during the evolution of the IKKγ proteins in metazoans.

Highlights

Selective autophagy is a catabolic process with which cellular material is targeted for degradation by lysosomes
Using an in silico approach to identify Drosophila proteins that interact with Atg8/LC3 proteins, here we show that Kenny, the Drosophila homolog of IKKγ/NEMO, is an Atg8a-interacting protein, and is required for the selective autophagic degradation of the IκB kinase (IKK) complex to prevent the constitutive activation of the immune deficiency (IMD) pathway by commensal bacteria
We observed that wild-type GFP-Kenny, but not its LC3-interacting region (LIR) motif-mutated counterpart, co-localized with active lysosomes as monitored by Cathepsin-L staining (Supplementary Fig. 1)

Summary

Introduction

Selective autophagy is a catabolic process with which cellular material is targeted for degradation by lysosomes. Selective autophagic degradation of the IκB kinase complex prevents constitutive activation of the immune deficiency pathway in response to commensal microbiota. Using an in silico approach to identify Drosophila proteins that interact with Atg8/LC3 proteins, here we show that Kenny, the Drosophila homolog of IKKγ/NEMO, is an Atg8a-interacting protein, and is required for the selective autophagic degradation of the IκB kinase (IKK) complex to prevent the constitutive activation of the IMD pathway by commensal bacteria. Our results describe a molecular mechanism of selective autophagy in Drosophila innate immunity, and suggest that pathogenrelated selective pressures may have induced the loss of a functional LIR motif in mammalian IKKγ through evolution

Methods

Results

Conclusion