Negative regulators of the RIG‐I‐like receptor signaling pathway

Abstract

SUMMARY Upon recognition of specific molecular patterns on viruses, bacteria and fungi, host cells trigger an innate immune response, which culminates in the production of type I interferons (IFN), pro-inflammatory cytokines and chemokines, and restricts pathogen replication and spread within the host. At each stage of the immune response, there are stimulatory and inhibitory signals that regulate the magnitude, quality, and character of the response. Positive regulation promotes an antiviral state to control and eventually clear infection whereas negative regulation dampens inflammation and prevents immune-mediated tissue damage. An over-exuberant innate immune response can lead to the destruction of cells and tissues, and the development of spontaneous autoimmunity. The RIG-I-like receptors (RLRs) retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) belong to a family of cytosolic host RNA helicases that recognize distinct non-self RNA signatures and trigger innate immune responses against several RNA virus infections. The RLR signaling pathway is tightly regulated to achieve a well-orchestrated response aimed at maximizing antiviral immunity and minimizing immune-mediated pathology. This review highlights contemporary findings on negative regulators of the RLR signaling pathway, with specific focus on the proteins and biological processes that directly regulate RIG-I, MDA5 and MAVS function.

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

“…A list of candidate immune function genes was curated from the following main sources: genome-wide study of rare copy number variants in 70 PML cases (Dis cohort) that impact immune function genes (data not shown), genes from the ClinVar database (43) using search terms "immune deficiency" and "immunodeficiency, " IUIS and other immunodeficiency reviews (29,30,(44)(45)(46)(47)(48)(49)(50), type I interferon pathway genes (51)(52)(53)(54)(55)(56)(57)(58), complement pathway genes (59), and JCV or PML linked biology (23,26,33,(60)(61)(62)(63)(64). The full list of 711 unique genes were cross-checked against genes that were found with DV-called variants in the Dis and/or Rep cohorts.…”

Breaking self-tolerance during autoimmunity and cancer immunity: Myeloid cells and type I IFN response regulation

“…Type I IFN induction downstream of ligand engagement by nucleic acid‐sensing PRRs relies on several core signaling pathways that either converge on activation of the transcription factor IRF7, in the case of TLR7, 8, and 9, or the transcription factor IRF3, in the case of TLR3, cGAS/STING, and RLR/MAVS. These signaling pathways, and the many genes that function to provide negative feedback on the strength of type I IFN induction, have been reviewed in detail elsewhere . In general, negative regulators of PRR signaling is accomplished through degradation or modification of key signaling proteins or modulation of protein trafficking that prevents signaling complexes from forming.…”

Genetic variants in IFIH1 and DDX58 influence hepatitis C virus clearance in Chinese Han population

“…As an important initiator of an innate immune response to RNA virus infection, RIG‐I‐like receptors (RLRs) play an indelible role in the host innate immune system . When the HCV invades the human body, the immune system is activated immediately to exert an antiviral effect.…”

“…During HCV infection, RIG‐I signaling activates the interferon regulatory factor‐3 (IRF‐3) and nuclear factor‐κB (NF‐κB). Finally, the production of type I interferon (INF‐I) and proinflammatory factor would clear HCV . Therefore, we speculated that DEAD (Asp‐Glu‐Ala‐Asp) box protein 58 (DDX58) and interferon‐induced helicase C domain‐containing protein 1 (IFIH1), as important members of RLRs, play an important role in influencing the susceptibility and clinical outcome of HCV infection …”

“…Finally, the production of type I interferon (INF-I) and proinflammatory factor would clear HCV. 8 Therefore, we speculated that DEAD (Asp-Glu-Ala-Asp) box protein 58 (DDX58) and interferon-induced helicase C domain-containing protein 1 (IFIH1), as important members of RLRs, play an important role in influencing the susceptibility and clinical outcome of HCV infection. 7,[9][10][11] With the development of genome-wide association studies in recent years, the study related to the gene polymorphisms of various diseases has become a hot topic.…”