WDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response.

RIG-I-MAVS signaling pathway plays a crucial role in defending against pathogen infection and maintaining immune balance. Upon detecting viral RNA, RIG-I triggers the formation of prion-like aggregates of the adaptor protein MAVS, which then activates the innate antiviral immune response. However, the mechanisms that regulate the aggregation of MAVS are not yet fully understood. Here, we identified WDR77 as a MAVS-associated protein, which negatively regulates MAVS aggregation. WDR77 binds to MAVS proline-rich region through its WD2-WD3-WD4 domain and inhibits the formation of prion-like filament of recombinant MAVS in vitro. In response to virus infection, WDR77 is recruited to MAVS to prevent the formation of its prion-like aggregates and thus downregulate RIG-I-MAVS signaling in cells. WDR77 deficiency significantly potentiates the induction of antiviral genes upon negative-strand RNA virus infections, and myeloid-specific Wdr77-deficient mice are more resistant to RNA virus infection. Our findings reveal that WDR77 acts as a negative regulator of the RIG-I-MAVS signaling pathway by inhibiting the prion-like aggregation of MAVS to prevent harmful inflammation.

The Endoplasmic Reticulum ATP13A1 is Essential for MAVS-Mediated Antiviral Innate Immunity.

RIG-I-MAVS signaling pathway is essential for efficient innate immune response against virus infection. Though many components have been identified in RIG-I pathway and it can be partially reconstituted in vitro, detailed mechanisms involved in cells are still unclear. Here, a genome-wide CRISPR-Cas9 screen is performed using an engineered cell line IFNB-P2A-GSDMD-N, and ATP13A1, a putative dislocase located on the endoplasmic reticulum, is identified as an important regulator of RIG-I pathway. ATP13A1 deficiency abolishes RIG-I-mediated antiviral innate immune response due to compromised MAVS stability and crippled signaling potency of residual MAVS. Moreover, it is discovered that MAVS is subject to protease-mediated degradation in the absence of ATP13A1. As homozygous Atp13a1 knockout mice result in developmental retardation and embryonic lethality, Atp13a1 conditional knockout mice are generated. Myeloid-specific Atp13a1-deficient mice are viable and susceptible to RNA virus infection. Collectively, the findings reveal that ATP13A1 is indispensable for the stability and activation of MAVS and a proper antiviral innate immune response.

Human STING Is Regulated by an Autoinhibitory Mechanism for Type I Interferon Production.

Stimulator of interferon genes (STING) plays a pivotal role in type I interferon-mediated innate immune response to the cytoplasmic detection of aberrant DNA. STING is a membrane protein localized in endoplasmic reticulum (ER), which upon stimulation translocates to Golgi apparatus and activates downstream signaling cascades. However, the mechanism regulating STING activity and significance of its intracellular traffic are not completely understood. Here we identify a novel region of human STING comprising thirteen residues within its C-terminal tail (CTT) for downstream nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. We also discover that STING CTT fragment can activate downstream signaling regardless of its ER localization. In addition, we reveal that ligand-binding domain (LBD) in the middle of STING binds and confers autoinhibition to its CTT for both NF-κB- and interferon regulatory factor 3-activation. Furthermore, STING LBD can inhibit the interferon-stimulating activity of STING CTT in trans and demonstrate a dominant negative effect on endogenous STING for interferon induction. We thus uncover an important autoinhibitory mechanism modulating STING activity.