Journal
AUTOPHAGY
Volume 15, Issue 8, Pages 1333-1355Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2019.1581009
Keywords
Autophagy; ATG14; BECN1; GABARAP; LIR; PIK3C3
Categories
Funding
- FRIBIOMED programme of the Research Council of Norway [214448]
- TOPPFORSK programme of the Research Council of Norway [249884]
- Norwegian Cancer Society [71043-PR-2006-0320]
- Francis Crick Institute from Cancer Research UK [FC001187, FC001999]
- UK Medical Research Council [FC001187, FC001999]
- Wellcome Trust [FC001187, FC001999]
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Autophagosome formation depends on a carefully orchestrated interplay between membrane-associated protein complexes. Initiation of macroautophagy/autophagy is mediated by the ULK1 (unc-51 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.
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