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Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs

Birgisdottir, AB; Mouilleron, S; Bhujabal, Z; Wirth, M; Sjottem, E; Evjen, G; Zhang, W; ... Johansen, T; + view all (2019) Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs. Autophagy , 15 (8) pp. 1333-1355. 10.1080/15548627.2019.1581009. Green open access

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Abstract

Autophagosome formation depends on a carefully orchestrated interplay between membraneassociated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc51 like autophagy activating kinase 1) protein kinase complex and the autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1). The latter contains PIK3C3/VPS34, PIK3R4/ VPS15, BECN1/Beclin 1 and ATG14 and phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PtdIns3P). Here, we show that PIK3C3, BECN1 and ATG14 contain functional LIR motifs and interact with the Atg8-family proteins with a preference for GABARAP and GABARAPL1. High resolution crystal structures of the functional LIR motifs of these core components of PtdIns3K-C1were obtained. Variation in hydrophobic pocket 2 (HP2) may explain the specificity for the GABARAP family. Mutation of the LIR motif in ATG14 did not prevent formation of the PtdIns3K-C1 complex, but blocked colocalization with MAP1LC3B/LC3B and impaired mitophagy. The ULK-mediated phosphorylation of S29 in ATG14 was strongly dependent on a functional LIR motif in ATG14. GABARAP-preferring LIR motifs in PIK3C3, BECN1 and ATG14 may, via coincidence detection, contribute to scaffolding of PtdIns3K-C1 on membranes for efficient autophagosome formation.

Type: Article
Title: Members of the autophagy class III phosphatidylinositol 3-kinase complex I interact with GABARAP and GABARAPL1 via LIR motifs
Open access status: An open access version is available from UCL Discovery
DOI: 10.1080/15548627.2019.1581009
Publisher version: https://doi.org/10.1080/15548627.2019.1581009
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Autophagy; ATG14; BECN1; GABARAP; LIR; PIK3C3
UCL classification: UCL
UCL > Provost and Vice Provost Offices > VP: Health
UCL > Provost and Vice Provost Offices > VP: Health > Translational Research Office
URI: https://discovery.ucl.ac.uk/id/eprint/10079122
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