TRAPPC11 functions in autophagy by recruiting ATG2B-WIPI4/WDR45 to preautophagosomal membranes

Traffic. 2019 May;20(5):325-345. doi: 10.1111/tra.12640. Epub 2019 Apr 9.

Abstract

TRAPPC11 has been implicated in membrane traffic and lipid-linked oligosaccharide synthesis, and mutations in TRAPPC11 result in neuromuscular and developmental phenotypes. Here, we show that TRAPPC11 has a role upstream of autophagosome formation during macroautophagy. Upon TRAPPC11 depletion, LC3-positive membranes accumulate prior to, and fail to be cleared during, starvation. A proximity biotinylation assay identified ATG2B and its binding partner WIPI4/WDR45 as TRAPPC11 interactors. TRAPPC11 depletion phenocopies that of ATG2 and WIPI4 and recruitment of both proteins to membranes is defective upon reduction of TRAPPC11. We find that a portion of TRAPPC11 and other TRAPP III proteins localize to isolation membranes. Fibroblasts from a patient with TRAPPC11 mutations failed to recruit ATG2B-WIPI4, suggesting that this interaction is physiologically relevant. Since ATG2B-WIPI4 is required for isolation membrane expansion, our study suggests that TRAPPC11 plays a role in this process. We propose a model whereby the TRAPP III complex participates in the formation and expansion of the isolation membrane at several steps.

Keywords: ATG2; LC3; TRAPP; TRAPPC11; TRAPPC12; TRAPPC8; WIPI4; autophagy; isolation membrane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagosomes / metabolism*
  • Autophagy
  • Autophagy-Related Proteins / metabolism*
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Fibroblasts / metabolism
  • HeLa Cells
  • Humans
  • Intracellular Membranes / metabolism
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Mutation
  • Protein Binding
  • Protein Transport
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • ATG2B protein, human
  • Autophagy-Related Proteins
  • Carrier Proteins
  • TRAPPC11 protein, human
  • Vesicular Transport Proteins
  • WDR45 protein, human

Grants and funding