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

Srikanth Battu,Avery August,Aleem Ahmed Khan,Seyed Ehtesham Hasnain,Rafiq Ahmad Khan,Bramanandam Manavathi,Saima Naz,Sumbul Afroz,Nooruddin Khan,Insaf Ahmed Qureshi,Weishan Huang,Jeevan Giddaluru,Saleem Yousuf Bhat,Saratchandra Singh Khumukcham,Douglas Green

doi:10.1371/journal.pbio.2005317

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.

Highlights

Dietary amino acid restriction, without malnutrition, offers enormous health benefits, including longevity of lifespan [1], acute stress resistance, increased insulin sensitivity, and modulation of inflammation [2,3]
The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
We observed a substantial reduction of interleukin 1β (IL-1β) in a dose- and time-dependent manner by HF (Fig 1A and S2A and S2B Fig), while tumor necrosis factor α (TNF-α) showed a decrease, and there was no suppressive effect on IL-6 during HF treatment (S2B and S2C Fig)

Summary

Introduction

Without malnutrition, offers enormous health benefits, including longevity of lifespan [1], acute stress resistance, increased insulin sensitivity, and modulation of inflammation [2,3]. General control nonderepressible 2 kinase (GCN2) is a well-known metabolic sensor, which senses amino acid starvation conditions and programs protein synthesis through activation of the homeostatic integrated stress response (ISR) [4]. Four distinct eukaryotic initiation factor 2 (eIF2) kinases—including GCN2, RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK), protein kinase R (PKR), and heme-regulated eIF2α kinase (HRI)—mediate the ISR [5]. GCN2 senses amino acid insufficiency, PERK is activated by endoplasmic reticulum stress, PKR senses viral double-stranded RNA (dsRNA), and HRI senses heme deprivation, respectively [6]

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Discussion

Conclusion