GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion

Dev Cell. 2019 Apr 8;49(1):145-155.e4. doi: 10.1016/j.devcel.2019.02.011. Epub 2019 Mar 14.

Abstract

Signal-sequence-lacking interleukin (IL)-1β, is cleaved by caspase-1 to mature mIL-1β, which is secreted, without entering the endoplasmic reticulum. We report that macrophages of GRASP55-/- mice are defective in mIL-1β secretion and retain it as intracellular aggregates. Intriguingly, GRASP55-/- macrophages are defective in the IRE1α branch of the unfolded protein response. This finding fits well with our data that inhibition of IRE1α also impairs mIL-1β secretion and causes its accumulation in intracellular aggregates. PERK inhibition, on the other hand, controls caspase-1-mediated conversion of proIL-1β to mIL-1β. These findings reveal translation-independent functions of PERK and IRE1α: PERK controls the production of mIL-1β, which is then followed by GRASP55 and IRE1α activity to keep mIL-1β in a secretion-competent form.

Keywords: GRASP; interleukin-1β (IL-1β); unconventional protein secretion (UPS); unfolded protein response (UPR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 1 / genetics
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / genetics
  • Endoribonucleases / genetics*
  • Golgi Matrix Proteins / genetics*
  • Interleukin-1beta / genetics*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Protein Aggregates / genetics*
  • Protein-Serine-Threonine Kinases / genetics*
  • Unfolded Protein Response / genetics
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / genetics*

Substances

  • DNA-Binding Proteins
  • Golgi Matrix Proteins
  • Gorasp2 protein, mouse
  • Interleukin-1beta
  • Lipopolysaccharides
  • Protein Aggregates
  • ERN1 protein, human
  • Ern1 protein, mouse
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases
  • Casp1 protein, mouse
  • Caspase 1