Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy

EMBO J. 2017 Jan 4;36(1):42-60. doi: 10.15252/embj.201695081. Epub 2016 Dec 8.

Abstract

Autophagy is a process delivering cytoplasmic components to lysosomes for degradation. Autophagy may, however, play a role in unconventional secretion of leaderless cytosolic proteins. How secretory autophagy diverges from degradative autophagy remains unclear. Here we show that in response to lysosomal damage, the prototypical cytosolic secretory autophagy cargo IL-1β is recognized by specialized secretory autophagy cargo receptor TRIM16 and that this receptor interacts with the R-SNARE Sec22b to recruit cargo to the LC3-II+ sequestration membranes. Cargo secretion is unaffected by downregulation of syntaxin 17, a SNARE promoting autophagosome-lysosome fusion and cargo degradation. Instead, Sec22b in combination with plasma membrane syntaxin 3 and syntaxin 4 as well as SNAP-23 and SNAP-29 completes cargo secretion. Thus, secretory autophagy utilizes a specialized cytosolic cargo receptor and a dedicated SNARE system. Other unconventionally secreted cargo, such as ferritin, is secreted via the same pathway.

Keywords: autophagy; galectins; inflammasome; lysosome; tuberculosis.

MeSH terms

  • Autophagy*
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Ferritins / metabolism
  • Humans
  • Interleukin-1beta / metabolism*
  • Microtubule-Associated Proteins / metabolism*
  • Monocytes / metabolism
  • Qa-SNARE Proteins / metabolism
  • Qb-SNARE Proteins / metabolism
  • Qc-SNARE Proteins / metabolism
  • R-SNARE Proteins / metabolism*
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases

Substances

  • DNA-Binding Proteins
  • Interleukin-1beta
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Qa-SNARE Proteins
  • Qb-SNARE Proteins
  • Qc-SNARE Proteins
  • R-SNARE Proteins
  • SNAP23 protein, human
  • SNAP29 protein, human
  • Sec22B protein, human
  • Transcription Factors
  • Tripartite Motif Proteins
  • Ferritins
  • TRIM16 protein, human
  • Ubiquitin-Protein Ligases