Amino acid starvation sensing dampens IL-1β production by activating riboclustering and autophagy

PLoS Biol. 2018 Apr 5;16(4):e2005317. doi: 10.1371/journal.pbio.2005317. eCollection 2018 Apr.

Abstract

Activation of the amino acid starvation response (AAR) increases lifespan and acute stress resistance as well as regulates inflammation. However, the underlying mechanisms remain unclear. Here, we show that activation of AAR pharmacologically by Halofuginone (HF) significantly inhibits production of the proinflammatory cytokine interleukin 1β (IL-1β) and provides protection from intestinal inflammation in mice. HF inhibits IL-1β through general control nonderepressible 2 kinase (GCN2)-dependent activation of the cytoprotective integrated stress response (ISR) pathway, resulting in rerouting of IL-1β mRNA from translationally active polysomes to inactive ribocluster complexes-such as stress granules (SGs)-via recruitment of RNA-binding proteins (RBPs) T cell-restricted intracellular antigen-1(TIA-1)/TIA-1-related (TIAR), which are further cleared through induction of autophagy. GCN2 ablation resulted in reduced autophagy and SG formation, which is inversely correlated with IL-1β production. Furthermore, HF diminishes inflammasome activation through suppression of reactive oxygen species (ROS) production. Our study unveils a novel mechanism by which IL-1β is regulated by AAR and further suggests that administration of HF might offer an effective therapeutic intervention against inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Amino Acids / deficiency*
  • Animals
  • Autophagy / drug effects
  • Autophagy / immunology*
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / drug therapy
  • Colitis / genetics
  • Colitis / immunology*
  • Gene Expression Regulation
  • Inflammasomes / genetics
  • Inflammasomes / immunology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology*
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Piperidines / pharmacology
  • Protein Biosynthesis*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / immunology
  • Protein Synthesis Inhibitors / pharmacology
  • Quinazolinones / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / immunology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Sodium Dodecyl Sulfate / administration & dosage
  • Starvation / genetics
  • Starvation / immunology
  • Stress, Physiological
  • T-Cell Intracellular Antigen-1 / genetics
  • T-Cell Intracellular Antigen-1 / immunology

Substances

  • Amino Acids
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • Piperidines
  • Protein Synthesis Inhibitors
  • Quinazolinones
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Reactive Oxygen Species
  • T-Cell Intracellular Antigen-1
  • Tia1 protein, mouse
  • Tial1 protein, mouse
  • Sodium Dodecyl Sulfate
  • Eif2ak4 protein, mouse
  • Protein Serine-Threonine Kinases
  • halofuginone

Grants and funding

Department of Biotechnology, Govt. of India http://www.dbtindia.nic.in/ (grant number BT/PR8624/MED/29/798/2013). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Nano Mission Council, Department of Science and Technology http://nanomission.gov.in/ (grant number SR/NM/NS-1040/2013(G)). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Department of Science and Technology, SERB http://www.serb.gov.in/home.php (grant number SB/YS/LS-163/2013). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. University Grants Commission, Government of India https://www.ugc.ac.in/ (grant number MRP-MAJOR-BIOT-2013-40689). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CSIR Junior Research Fellowship http://csirhrdg.res.in/. Supports Author SB. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JC Bose National Fellowship, Department of Science and Technology, Ministry of Science & Technology, Government of India. http://serb.gov.in/jcbn.php. Supports Author SEH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.