NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses

Guo et al., 2016, Cell Host & Microbe 19, 515–528.

Speaker: Wei-Ren Cheng (鄭惟仁)                                Time: 14:10~15:00, Sep 14, 2016

Commentator: Dr. Shainn-Wei Wang (王憲威 老師)    Place: Room 601

Abstract

STING-dependent DNA sensing pathway induces type I interferon production which provides antiviral responses against HIV infection [1]. The expression of NLRX1, a NOD-like receptor that inhibits MAVS-mediated type I interferon production, is decreased in HIV-infected patients [2, 3]. However, the function of NLRX1 in modulating HIV-induced type I interferon production remains unclear. The authors investigated the importance of NLRX1 in HIV infection by knocking down NLRX1 expression in cells. NLRX1 knockdown not only reduced HIV infection by inhibiting viral DNA import but also enhanced type I interferon expression. They further found that HIV induced type I interferon production via its reverse-transcribed DNA, but not via its RNA. NLRX1 inhibited STING-dependent DNA sensing pathway which was stimulated by viral DNA. To explore how NLRX1 interferes this pathway, the interaction between NLRX1 and STING was examined. Results showed that NLRX1 competed with TBK1 for STING interaction. These results indicate that NLRX1 also acts as a negative regulator in STING-dependent DNA sensing pathway and type I interferon production in HIV infection. The authors further investigated the role of NLRX1 in other DNA virus infections. Consistent with HIV infection, the innate immune signaling pathway also inhibited by NLRX1 in herpes simplex virus type I- or vaccinia virus-infected cells. They further showed that, in mice infected with herpes simplex virus type I, NLRX1 reduced not only the survival rate but also the type I interferon production. In summary, NLRX1 functions as a negative regulator in STING-dependent pathway and disrupts innate immune response against HIV and other DNA viruses. This finding provides a new strategy for innate immunity regulation by targeting NLRX1.

References:

1. Gao, D., et al., Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science, 2013. 341(6148): p. 903-6.

2. Allen, I.C., et al., NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-kappaB signaling pathways. Immunity, 2011. 34(6): p. 854-65.

3. Nasi, M., et al., Analysis of inflammasomes and antiviral sensing components reveals decreased expression of NLRX1 in HIV-positive patients assuming efficient antiretroviral therapy. AIDS, 2015. 29(15):p. 1937-41.