RNA sensor LGP 2 inhibits TRAF ubiquitin ligase to negatively regulate innate immune signaling

Abstract

The production of type I interferon (IFN) is essential for cellular barrier functions and innate and adaptive antiviral immunity. In response to virus infections, RNA receptors RIG-I and MDA5 stimulate a mitochondria-localized signaling apparatus that uses TRAF family ubiquitin ligase proteins to activate master transcription regulators IRF3 and NFκB, driving IFN and antiviral target gene expression. Data indicate that a third RNA receptor, LGP2, acts as a negative regulator of antiviral signaling by interfering with TRAF family proteins. Disruption of LGP2 expression in cells results in earlier and overactive transcriptional responses to virus or dsRNA LGP2 associates with the C-terminus of TRAF2, TRAF3, TRAF5, and TRAF6 and interferes with TRAF ubiquitin ligase activity. TRAF interference is independent of LGP2 ATP hydrolysis, RNA binding, or its C-terminal domain, and LGP2 can regulate TRAF-mediated signaling pathways in , including IL-1β, TNFα, and cGAMP These findings provide a unique mechanism for LGP2 negative regulation through TRAF suppression and extend the potential impact of LGP2 negative regulation beyond the IFN antiviral response.

DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-κB and sensitize to alkylating chemotherapy

“…LGP2 was recently reported to inhibit NF-κB activity independent of RNA binding via its interaction with TNF receptor-associated factor (TRAF) proteins [43]. The ability of LGP2 to regulate NF-κB independent of RNA binding is consistent with our finding that loss of DDX39B activated NF-κB without altering cytoplasmic dsRNA content.…”

“…MAVS, and TRIF. Although these three factors are functionally interrelated in that LGP2 regulates MAVS signaling [43], and MAVS and TRIF together modulate the downstream response [9,44], DDX39B specifically interacted with LGP2, not MAVS or TRIF.…”

Double-Stranded RNA Sensors and Modulators in Innate Immunity

“…Activated MAVS then recruits multiple signaling molecules, including TRAFs, TBK1, and IRF3/7, leading to the transcriptional upregulation of type I interferons and other proinflammatory cytokines (17,18). Unlike RIG-I and MDA5, LGP2 does not directly activate MAVS but is thought to positively and negatively regulate MDA5 and RIG-I (19)(20)(21), respectively, although additional regulatory activities were also reported (22). Despite sharing the same downstream signaling pathways, RIG-I and MDA5 play nonredundant roles by recognizing largely distinct groups of viral RNAs (17,18).…”

Slicing and dicing viruses: antiviral RNA interference in mammals

“…LGP2 lacks CARDs and is unable to induce signalling via MAVS. It is thought to act by modulating responses by the other RLRs (Bruns & Horvath, ; Bruns et al, ; Parisien et al, ).…”