Intrinsic lipid binding activity of ATG16L1 supports efficient membrane anchoring and autophagy

Leo J Dudley, Ainara G Cabodevilla, Agata N Makar, Martin Sztacho, Tim Michelberger, Joseph A Marsh, Douglas R Houston, Sasha Martens, Xuejun Jiang, Noor Gammoh

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Membrane targeting of autophagy‐related complexes is an important step that regulates their activities and prevents their aberrant engagement on non‐autophagic membranes. ATG16L1 is a core autophagy protein implicated at distinct phases of autophagosome biogenesis. In this study, we dissected the recruitment of ATG16L1 to the pre‐autophagosomal structure (PAS) and showed that it requires sequences within its coiled‐coil domain (CCD) dispensable for homodimerisation. Structural and mutational analyses identified conserved residues within the CCD of ATG16L1 that mediate direct binding to phosphoinositides, including phosphatidylinositol 3‐phosphate (PI3P). Mutating putative lipid binding residues abrogated the localisation of ATG16L1 to the PAS and inhibited LC3 lipidation. On the other hand, enhancing lipid binding of ATG16L1 by mutating negatively charged residues adjacent to the lipid binding motif also resulted in autophagy inhibition, suggesting that regulated recruitment of ATG16L1 to the PAS is required for its autophagic activity. Overall, our findings indicate that ATG16L1 harbours an intrinsic ability to bind lipids that plays an essential role during LC3 lipidation and autophagosome maturation.
Original languageEnglish
Article numbere100554
Number of pages16
JournalEMBO Journal
Issue number9
Early online date1 Apr 2019
Publication statusPublished - 2 May 2019

Keywords / Materials (for Non-textual outputs)

  • ATG16L1
  • autophagy
  • PI3P
  • phagophore
  • coiled-coil domain
  • lipids
  • membrane


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