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.
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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-pp.ucl.ac.uk/id/eprint/10079122 |
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