RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation

Abstract

The activation of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic innate sensor for viral RNA, is tightly regulated to maintain immune homeostasis properly and prevent excessive inflammatory reactions other than initiation of antiviral innate response to eliminate RNA virus effectively. Posttranslational modifications, particularly ubiquitination, are crucial for regulation of RIG-I activity. Increasing evidence suggests that E3 ligases play important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Here we identify that E3 ubiquitin ligase RING finger protein 122 (RNF122) directly interacts with mouse RIG-I through MS screening of RIG-Iinteracting proteins in RNA virus-infected cells. The transmembrane domain of RNF122 associates with the caspase activation and recruitment domains (CARDs) of RIG-I; this interaction effectively triggers RING finger domain of RNF122 to deliver the Lys-48-linked ubiquitin to the Lys115 and Lys146 residues of RIG-I CARDs and promotes RIG-I degradation, resulting in a marked inhibition of RIG-I downstream signaling. RNF122 is widely expressed in various immune cells, with preferential expression in macrophages. Deficiency of RNF122 selectively increases RIG-I-triggered production of type I IFNs and proinflammatory cytokines in macrophages. RNF122-deficient mice exhibit more resistance against lethal RNA virus infection, with increased production of type I IFNs. Thus, we demonstrate that RNF122 acts as a selective negative regulator of RIG-I-triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I. Our study outlines a way for E3 ligase to regulate innate sensor RIG-I for the control of antiviral innate immunity.RIG-I | E3 ligase | RNF122 | innate immunity | type I interferon

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

“…We first hypothesized that this E3-ubiquitin ligase could be involved in the regulation of RIG-I, a tumor suppressor that controls differentiation, apoptosis and tumorigenesis processes. This idea was supported by the evidence that RIG-I stability and activity is modulated by the E3-ligases RNF122 [34] and MEX3C (the MEX3A paralogue) [20], whose mRNA expression levels were found to be up-regulated in GB (Supplementary Figure S1B,C and Figure 2C) [20,28,34].…”

RIG-I-like receptors: their regulation and roles in RNA sensing

“…Conversely, RIG-I stability is regulated by classical degradative K48-linked polyubiquitylation mediated by at least three E3 ligases -Cbl, ring finger protein 122 (RNF122) and RNF125 -whereas ubiquitylation mediated by linear ubiquitin chain assembly complex (LUBAC) negatively affects the stability of TRIM25 and its interaction with RIG-I [114][115][116][117] (fiG. 3).…”

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

“…For instance, the RING-finger protein 125 (RNF125), together with the ubiquitin E2 ligase UbcH5, conjugate K48-linked ubiquitin to RIG-I and MAVS, targeting them for proteasomal degradation and thereby inhibiting downstream signaling (64). Similarly, RNF122 was recently demonstrated to mediate the proteasomal degradation of RIG-I by delivering the K48-linked ubiquitin to RIG-I CARDs (65). The linear ubiquitin assembly complex (LUBAC) has been shown to promote K48 pUb of TRIM25, leading to its degradation (66).…”