The autophagy protein ATG16L1 cooperates with IFT20 and INPP5E to regulate the turnover of phosphoinositides at the primary cilium.

Asma Boukhalfa,Patrice Codogno,Nicolas Dupont,Federica Roccio,Etienne Morel

doi:10.1016/j.celrep.2021.109045

Abstract

The primary cilium (PC) regulates signalization linked to external stress sensing. Previous works established a functional interplay between the PC and the autophagic machinery. When ciliogenesis is promoted by serum deprivation, the autophagy protein ATG16L1 and the ciliary protein IFT20 are co-transported to the PC. Here, we demonstrate that IFT20 and ATG16L1 are part of the same complex requiring the WD40 domain of ATG16L1 and a Y-E-F-I motif in IFT20. We show that ATG16L1-deficient cells exhibit aberrant ciliary structures, which accumulate PI4,5P2, whereas PI4P, a lipid normally concentrated in the PC, is absent. Finally, we demonstrate that INPP5E, a phosphoinositide-associated phosphatase responsible for PI4P generation, interacts with ATG16L1 and that a perturbation of the ATG16L1/IFT20 complex alters its trafficking to the PC. Altogether, our results reveal a function of ATG16L1 in ciliary lipid and protein trafficking, thus directly contributing to proper PC dynamics and functions.

Highlights

The primary cilium (PC) is a microtubule-based antenna present at the surface of many cell types
We functionally document the previously reported ATG16L1-IFT20 interaction (Pampliega et al, 2013), and we report that ATG16L1 dialogs with the phosphoinositide phosphatase INPP5E, which is associated with the Joubert syndrome, a recessive neurodevelopmental ciliopathy (Bielas et al, 2009)
We show that ATG16L1 is a PI4P-interacting protein and that, in the absence of ATG16L1, PI(4,5)P2 accumulates at the expense of PI4P and affects ciliogenesis by altering PC organization and signaling functions, leading to a giant cilium-like structure

Summary

Introduction

The primary cilium (PC) is a microtubule-based antenna present at the surface of many cell types. The PC is organized into three substructures: the basal body that matures from the mother centriole, the axoneme that protrudes from the cell surface, and the transitory zone that allows proteins to be transported into the axoneme from the cytosol (Satir et al, 2010). Ciliogenesis depends on intraflagellar transport (IFT) particles (Goetz and Anderson, 2010; Satir et al, 2010; Malicki and Johnson, 2017; Nachury and Mick, 2019). Defective PC function is the cause of many human diseases known as ciliopathies These diseases can target several organs and mostly lead to developmental disorders (Braun and Hildebrandt, 2017; Reiter and Leroux, 2017)

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