Amino acid starvation sensing dampens IL-1β production by activating riboclustering and autophagy
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...
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| Published in | PLoS biology Vol. 16; no. 4; p. e2005317 |
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| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Public Library of Science
05.04.2018
Public Library of Science (PLoS) |
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| 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. |
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| AbstractList | 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.
Reduced intake of food (also known as dietary restriction) without malnutrition has been shown to benefit health in humans and animals, including an increase in life expectancy, metabolic fitness, and resistance to acute stress. Recent studies have attributed the benefits associated with dietary restriction to the reduced intake of amino acids. However, the underlying mechanisms through which amino acid restriction regulates various homeostatic processes are poorly defined. Here, we show that activation of amino acid starvation response (AAR) by the small molecule Halofuginone (HF) results in a significant inhibition of production of interleukin 1β (IL-1β), a proinflammatory mediator. We find that AAR provides protection from intestinal inflammation–associated pathology in a mouse model of colitis through a novel mechanism involving the formation of riboclusters (groups of RNA-binding proteins (RBPs) and stalled mRNA complexes) and autophagy. We further show that HF-mediated inhibition in IL-1β production is dependent on general control nonderepressible 2 kinase (GCN2), an amino acid deprivation sensor. This study provides the mechanisms regulating AAR-induced benefits in the context of inflammation and further suggests that the administration of HF might offer an effective therapeutic intervention against inflammatory diseases in mammals. 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.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. 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. |
| Author | Afroz, Sumbul Bhat, Saleem Yousuf Manavathi, Bramanandam August, Avery Khan, Nooruddin Khan, Rafiq Ahmad Hasnain, Seyed Ehtesham Khan, Aleem Ahmed Giddaluru, Jeevan Qureshi, Insaf Ahmed Huang, Weishan Khumukcham, Saratchandra Singh Battu, Srikanth Naz, Saima |
| AuthorAffiliation | 1 Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India 3 Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America 5 JH-Institute of Molecular Medicine, Jamia Hamdard University, Hamdard Nagar, New Delhi, India 2 Centre for Liver Research and Diagnostics, Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India 6 Molecular Infection and Functional Biology Laboratory, Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India 4 Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India 7 Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India St. Jude Childrens Research Hospital, Memphis, United States of America |
| AuthorAffiliation_xml | – name: 6 Molecular Infection and Functional Biology Laboratory, Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India – name: 7 Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India – name: St. Jude Childrens Research Hospital, Memphis, United States of America – name: 1 Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India – name: 2 Centre for Liver Research and Diagnostics, Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India – name: 5 JH-Institute of Molecular Medicine, Jamia Hamdard University, Hamdard Nagar, New Delhi, India – name: 3 Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America – name: 4 Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India |
| Author_xml | – sequence: 1 givenname: Srikanth surname: Battu fullname: Battu, Srikanth – sequence: 2 givenname: Sumbul surname: Afroz fullname: Afroz, Sumbul – sequence: 3 givenname: Jeevan surname: Giddaluru fullname: Giddaluru, Jeevan – sequence: 4 givenname: Saima surname: Naz fullname: Naz, Saima – sequence: 5 givenname: Weishan surname: Huang fullname: Huang, Weishan – sequence: 6 givenname: Saratchandra Singh surname: Khumukcham fullname: Khumukcham, Saratchandra Singh – sequence: 7 givenname: Rafiq Ahmad surname: Khan fullname: Khan, Rafiq Ahmad – sequence: 8 givenname: Saleem Yousuf surname: Bhat fullname: Bhat, Saleem Yousuf – sequence: 9 givenname: Insaf Ahmed surname: Qureshi fullname: Qureshi, Insaf Ahmed – sequence: 10 givenname: Bramanandam surname: Manavathi fullname: Manavathi, Bramanandam – sequence: 11 givenname: Aleem Ahmed surname: Khan fullname: Khan, Aleem Ahmed – sequence: 12 givenname: Avery surname: August fullname: August, Avery – sequence: 13 givenname: Seyed Ehtesham surname: Hasnain fullname: Hasnain, Seyed Ehtesham – sequence: 14 givenname: Nooruddin surname: Khan fullname: Khan, Nooruddin |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29621237$$D View this record in MEDLINE/PubMed |
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