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

dc.contributor.author Battu, Srikanth
dc.contributor.author Afroz, Sumbul
dc.contributor.author Giddaluru, Jeevan
dc.contributor.author Naz, Saima
dc.contributor.author Huang, Weishan
dc.contributor.author Khumukcham, Saratchandra Singh
dc.contributor.author Khan, Rafiq Ahmad
dc.contributor.author Bhat, Saleem Yousuf
dc.contributor.author Qureshi, Insaf Ahmed
dc.contributor.author Manavathi, Bramanandam
dc.contributor.author Khan, Aleem Ahmed
dc.contributor.author August, Avery
dc.contributor.author Hasnain, Seyed Ehtesham
dc.contributor.author Khan, Nooruddin
dc.date.accessioned 2022-03-27T05:19:33Z
dc.date.available 2022-03-27T05:19:33Z
dc.date.issued 2018-04-05
dc.description.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.
dc.identifier.citation PLoS Biology. v.16(4)
dc.identifier.issn 15449173
dc.identifier.uri 10.1371/journal.pbio.2005317
dc.identifier.uri https://dx.plos.org/10.1371/journal.pbio.2005317
dc.identifier.uri https://dspace.uohyd.ac.in/handle/1/8078
dc.title Amino acid starvation sensing dampens IL-1β production by activating riboclustering and autophagy
dc.type Journal. Article
dspace.entity.type
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