A loosened gating mechanism of RIG-I leads to autoimmune disorders

Abstract

DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased susceptibility to Singleton-Merten syndrome (SMS) defects, resulting in tissue-specific (mild) and classic (severe) phenotypes. The coupling between RNA recognition and conformational changes is central to RIG-I RNA proofreading, but the molecular determinants leading to dissociated disease phenotypes remain unknown. Herein, we employed hydrogen/deuterium exchange mass spectrometry (HDX-MS) and single molecule magnetic tweezers (MT) to precisely examine how subtle conformational changes in the helicase insertion domain (HEL2i) promote impaired ATPase and erroneous RNA proofreading activities. We showed that the mutations cause a loosened latch-gate engagement in apo RIG-I, which in turn gradually dampens its self RNA (Cap2 moiety:m7G cap and N1-2-2′-O-methylation RNA) proofreading ability, leading to increased immunopathy. These results reveal HEL2i as a unique checkpoint directing two specialized functions, i.e. stabilizing the CARD2-HEL2i interface and gating the helicase from incoming self RNAs; thus, these findings add new insights into the role of HEL2i in the control of antiviral innate immunity and autoimmunity diseases.

Dynamic Evolution of Avian RNA Virus Sensors: Repeated Loss of RIG-I and RIPLET

“…The RIG-I losses presented here are intriguing due to their high number, which suggests a long-term continuing tendency for RLR losses during avian evolution. Notably, in humans both MDA5 and RIG-I mutations have been connected to autoimmune disorders caused by the recognition of self RNA structures [ 67 , 68 ]. A tendency to avoid such inappropriate sensing might represent another type of pressure for sensor loss.…”

Clinical Implications of a New DDX58 Pathogenic Variant That Causes Lupus Nephritis due to RIG-I Hyperactivation

“…22,23 The other two SMS DDX58 variants (E510V and Q517H) happened in the HEL-2i domain (Supplemental Figure 2A), weakening the RNA proofreading capabilities, failing to distinguish self from nonself RNA, and inducing hyperactivation of RIG-I. 24 However, the R109C variant causing LN, located in the CARD2 domain (Supplemental Figure 2A), leads to defective CARDs binding and loss of autoinhibition of RIG-I. The different mechanisms result in various activation of RIG-I and a distinct pattern of upregulation of downstream IFN signaling, as a consequence, presenting with different phenotypes.…”

The molecular language of RNA 5′ ends: guardians of RNA identity and immunity

“…The disease manifestations include glaucoma, calcification of the aorta, and dental and skin issues, such as psoriasis. Mechanistically, those gain-of-function mutations lead to a constitutively activated RIG-I form, unable to dissociate from endogenous self-RNAs, resulting in constant IFN signaling ( Devarkar et al 2018 ; Lässig et al 2018 ; Lei et al 2022 ). Which endogenous RNAs drive IFN activation in the context of this syndrome are still unknown.…”