Autophagy-based Unconventional Secretory Pathway for Extracellular Delivery of IL-1β

EMBO J. 2011 Nov 8;30(23):4701-11. doi: 10.1038/emboj.2011.398.

Abstract

Autophagy controls the quality and quantity of the eukaryotic cytoplasm while performing two evolutionarily highly conserved functions: cell-autonomous provision of energy and nutrients by cytosol autodigestion during starvation, and removal of defunct organelles and large aggregates exceeding the capacity of other cellular degradative systems. In contrast to these autodigestive processes, autophagy in yeast has additional, biogenesis functions. However, no equivalent biosynthetic roles have been described for autophagy in mammals. Here, we show that in mammalian cells, autophagy has a hitherto unappreciated positive contribution to the biogenesis and secretion of the proinflammatory cytokine IL-1β via an export pathway that depends on Atg5, inflammasome, at least one of the two mammalian Golgi reassembly stacking protein (GRASP) paralogues, GRASP55 (GORASP2) and Rab8a. This process, which is a type of unconventional secretion, expands the functional manifestations of autophagy beyond autodigestive and quality control roles in mammals. It enables a subset of cytosolic proteins devoid of signal peptide sequences, and thus unable to access the conventional pathway through the ER, to enter an autophagy-based secretory pathway facilitating their exit from the cytoplasm.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Autophagy-Related Protein 5
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • HMGB1 Protein / metabolism
  • Inflammasomes / metabolism
  • Interleukin-18 / metabolism
  • Interleukin-1beta* / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins / metabolism
  • Macrolides / pharmacology
  • Macrophages / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Nigericin / pharmacology
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • Secretory Pathway / drug effects
  • Secretory Pathway / physiology
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Carrier Proteins
  • HMGB1 Protein
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • MAP1LC3 protein, mouse
  • Macrolides
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Rab8a protein, mouse
  • tamalin protein, mouse
  • bafilomycin A1
  • rab GTP-Binding Proteins
  • Nigericin