Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins

Martina Wirth,Stéphane Mouilleron,Terje Johansen,Minoo Razi,Dhira Joshi,Nicola O'Reilly,Wenxin Zhang,Lynet Nyoni,Sharon A Tooze

doi:10.1038/s41467-019-10059-6

Martina Wirth, Stéphane Mouilleron + Show 7 more

Open Access

https://doi.org/10.1038/s41467-019-10059-6

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Abstract

Autophagy is an essential recycling and quality control pathway. Mammalian ATG8 proteins drive autophagosome formation and selective removal of protein aggregates and organelles by recruiting autophagy receptors and adaptors that contain a LC3-interacting region (LIR) motif. LIR motifs can be highly selective for ATG8 subfamily proteins (LC3s/GABARAPs), however the molecular determinants regulating these selective interactions remain elusive. Here we show that residues within the core LIR motif and adjacent C-terminal region as well as ATG8 subfamily-specific residues in the LIR docking site are critical for binding of receptors and adaptors to GABARAPs. Moreover, rendering GABARAP more LC3B-like impairs autophagy receptor degradation. Modulating LIR binding specificity of the centriolar satellite protein PCM1, implicated in autophagy and centrosomal function, alters its dynamics in cells. Our data provides new mechanistic insight into how selective binding of LIR motifs to GABARAPs is achieved, and elucidate the overlapping and distinct functions of ATG8 subfamily proteins.

Highlights

Autophagy is an essential recycling and quality control pathway
Pericentriolar material 1 (PCM1) binds to GABARAP via a C terminally extended LC3-interacting region (LIR) motif
We recently showed that the centriolar satellite (CS) protein PCM1 binds directly to GABARAP through a canonical LIR motif regulating GABARAPspecific autophagosome formation and GABARAP stability[26]

Summary

Introduction

Mammalian ATG8 proteins drive autophagosome formation and selective removal of protein aggregates and organelles by recruiting autophagy receptors and adaptors that contain a LC3-interacting region (LIR) motif. LIR motifs can be highly selective for ATG8 subfamily proteins (LC3s/GABARAPs), the molecular determinants regulating these selective interactions remain elusive. We show that residues within the core LIR motif and adjacent C-terminal region as well as ATG8 subfamily-specific residues in the LIR docking site are critical for binding of receptors and adaptors to GABARAPs. rendering GABARAP more LC3B-like impairs autophagy receptor degradation. A growing number of ATG8 interactors are autophagy adaptors, which are not degraded by autophagy and fulfilling diverse functions ranging from regulation of autophagosome formation (e.g., ULK complex17,18) and fusion with the lysosome (e.g., PLEKHM119) to autophagosome transport (e.g., FYCO120)

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