PtdIns(4,5)P2 signaling regulates ATG14 and autophagy

Xiaojun Tan, Narendra Thapa, Yihan Liao, Suyong Choi, Richard A. Anderson

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Autophagy is a regulated self-digestion pathway with fundamental roles in cell homeostasis and diseases. Autophagy is regulated by coordinated actions of a series of autophagy-related (ATG) proteins. The Barkor/ATG14(L)-VPS34 (a class III phosphatidylinositol 3-kinase) complex and its product phosphatidylinositol 3-phosphate [PtdIns(3)P] play key roles in autophagy initiation. ATG14 contains a C-terminal Barkor/ATG14(L) autophagosome-targeting sequence (BATS) domain that senses the curvature of PtdIns(3)P-containing membrane. The BATS domain also strongly binds PtdIns(4,5)P2 , but the functional significance has been unclear. Here we show that ATG14 specifically interacts with type Iγ PIP kinase isoform 5 (PIPKIγi5), an enzyme that generates PtdIns(4,5)P2 in mammalian cells. Autophagosomes have associated PIPKIγi5 and PtdIns(4,5)P2 that are colocalized with late endosomes and the endoplasmic reticulum. PtdIns(4,5)P2 generation at these sites requires PIPKIγi5. Loss of PIPKIγi5 results in a loss of ATG14, UV irradiation resistance-associated gene, and Beclin 1 and a block of autophagy. PtdIns(4,5)P2 binding to the ATG14-BATS domain regulates ATG14 interaction with VPS34 and Beclin 1, and thus plays a key role in ATG14 complex assembly and autophagy initiation. This study identifies an unexpected role for PtdIns(4,5)P2 signaling in the regulation of ATG14 complex and autophagy.

Original languageEnglish (US)
Pages (from-to)10896-10901
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number39
DOIs
StatePublished - Sep 27 2016
Externally publishedYes

Keywords

  • ATG14
  • Atg14-bats domain
  • Autophagy
  • PIPKIγi5
  • PtdIns(4 5)p2

ASJC Scopus subject areas

  • General

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