Selective autophagy controls innate immune response through a TAK1/TAB2/SH3PX1 axis.

Panagiotis Tsapras,Marta Geborys,Antonia P Sagona,Anne-Claire Jacomin,Ioannis P Nezis,Stavroula Petridi,Selina Chan,Pascal Meier

doi:10.1016/j.celrep.2021.110286

Panagiotis Tsapras, Marta Geborys + Show 6 more

Open Access

https://doi.org/10.1016/j.celrep.2021.110286

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Abstract

Selective autophagy is a catabolic route that 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 selective autophagy substrates that interact with the autophagy protein Atg8a. We also present 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 removal of the Tak1/Tab2 signaling complex by selective autophagy. This 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.

Highlights

The anti-inflammatory pathways of the host innate immune response comprise the most ancient system of a frontline multi-layered defense against invading pathogens
The analysis yielded several Atg8a-interacting proteins (Table S1) in over 103 million interactions tested. For each of those positive hits, the screen mapped a region termed selected interaction domain (SID), which corresponded to where the Atg8a binding was detected (Figures S1 and S2). We classified these interactions into three groups: (1) proteins that had already been experimentally verified to bind Atg8a, such as Atg1 (Alemu et al, 2012), diabetes and obesity regulated (Dor) (Francis et al, 2010; Nowak et al, 2009), refractory to Sigma P (Ref(2)P) (Jain et al, 2015), and Kenny (Tusco et al, 2017); (2) Drosophila proteins for which their mammalian homologs are known to associate with ATG8-family members, such as Ankyrin 2 (Ank2) (Li et al, 2018), Atg4a (Kirisako et al, 2000), and neural precursor cell-expressed developmentally down-regulated protein 4 (Nedd4) (Sun et al, 2017); and (3) undescribed Atg8a-interacting proteins (Figures S1 and S2; Table S1), such as Trc and Tak1
We observed that the 6xHis (His)-tagged Trc prey co-precipitated with the wild-type (WT) recombinant glutathione S transferase (GST):Atg8a bait, indicating a direct protein-protein interaction (Figure S3A)

Summary

Introduction

The anti-inflammatory pathways of the host innate immune response comprise the most ancient system of a frontline multi-layered defense against invading pathogens. Autophagy has been shown to have a role in dampening the NF-kB signal of innate immune responses against invading pathogens, or cytosol-detected DNA of mitochondrial or viral origin (Nakahira et al, 2011; Prabakaran et al, 2018; Tusco et al, 2017). This is achieved by removing key signal transduction components from these cascades (Nakahira et al, 2011; Prabakaran et al, 2018; Tusco et al, 2017)

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