IRF3-binding lncRNA-ISIR strengthens interferon production in viral infection and autoinflammation.

Junfang Xu,Zhiqing Li,Minghong Jiang,Yuanwu Ma,Xuetao Cao,Wei Liu,Qihang Zhao,Mingyue Wen,Dan Han,Lianfeng Zhang,Pin Wang,Xuan Zhang,Zemeng Li

doi:10.1016/j.celrep.2021.109926

Abstract

Interferon regulatory factor 3 (IRF3) is an essential transductor for initiation of many immune responses. Here, we show that lncRNA-ISIR directly binds IRF3 to promote its phosphorylation, dimerization, and nuclear translocation, along with enhanced target gene productions. Invivo lncRNA-ISIR deficiency results in reduced IFN production, uncontrolled viral replication, and increased mortality. The human homolog, AK131315, also binds IRF3 and promotes its activation. More important, AK131315 expression is positively correlated with type I interferon (IFN-I) level and severity in patients with lupus. Mechanistically, in resting cells, IRF3 is bound to suppressor protein Flightless-1 (Fli-1), which keeps its inactive state. Upon infection, IFN-I-induced lncRNA-ISIR binds IRF3 at DNA-binding domain in cytoplasm and removes Fli-1's association from IRF3, consequently facilitating IRF3 activation. Our results demonstrate that IFN-I-inducible lncRNA-ISIR feedback strengthens IRF3 activation by removing suppressive Fli-1 inimmune responses, revealing a method of lncRNA-mediated modulation of transcription factor (TF) activation.

Highlights

The orchestrated innate immune responses, especially the appropriate induction of type I interferon (IFN-I), play a vital role in host defense against many infections, especially viral infection, and in the pathogenesis of many autoimmune diseases
The immune signaling cascades are activated by signaling adaptors, including retinoic acid-inducible gene I (RIG-I)-mitochondrial antiviral-signaling protein (MAVS), cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), and TLR3-TIR domain-containing adaptor-inducing b interferon (TRIF), to recruit and activate TANK-binding kinase 1 (TBK1), which phosphorylates transcription factor (TF) Interferon regulatory factor 3 (IRF3) (Seth et al, 2005; Xiao and Fitzgerald, 2013; Liu et al, 2015; Matsumoto et al, 2011)
Through formaldehyde-crosslinked RNA immunoprecipitation (FA-CLIP) and RNA sequencing, we identify one undescribed IRF3-binding long noncoding RNAs (lncRNAs), lncRNA-ISIR, which is induced upon viral infection and derived from an intergenic noncoding gene

Summary

Introduction

The orchestrated innate immune responses, especially the appropriate induction of type I interferon (IFN-I), play a vital role in host defense against many infections, especially viral infection, and in the pathogenesis of many autoimmune diseases. The immune signaling cascades are activated by signaling adaptors, including RIG-I-mitochondrial antiviral-signaling protein (MAVS), cGAS-stimulator of interferon genes (STING), and TLR3-TIR domain-containing adaptor-inducing b interferon (TRIF), to recruit and activate TANK-binding kinase 1 (TBK1), which phosphorylates transcription factor (TF) IRF3 (Seth et al, 2005; Xiao and Fitzgerald, 2013; Liu et al, 2015; Matsumoto et al, 2011). It has been reported that phosphorylation on the pLxIS motif of adaptors MAVS, STING, and TRIF, leads to the recruitment of

Methods

Results

Discussion

Conclusion