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The antiviral innate immunity is the first line of host defense against viral infection. Mitochondrial antiviral signaling protein (MAVS, also named Cardif/IPS-1/VISA) is a critical protein in RNA virus-induced antiviral signaling pathways. Our previous research suggested that E3 ubiquitin-protein ligases RING-finger protein (RNF90) negatively regulate cellular antiviral responses by targeting STING for degradation, though its role in RNA virus infection remains unknown. This study demonstrated that RNF90 negatively regulated RNA virus-triggered antiviral innate immune responses in RNF90-silenced PMA-THP1 cells, RNF90-deficient cells (including HaCaTs, MEFs, and BMDMs), and RNF90-deficient mice. However, RNF90 regulated RNA virus-triggered antiviral innate immune responses independent of STING. RNF90 promoted K48-linked ubiquitination of MAVS and its proteasome-dependent degradation, leading to the inhibition of innate immune responses. Altogether, our findings suggested a novel function and mechanism of RNF90 in antiviral innate immunity. [ABSTRACT FROM AUTHOR]

Mediator of IRF3 activation (MITA, also named as STING/ERIS/MPYS/TMEM173), is essential to DNA virus- or cytosolic DNA-triggered innate immune responses. In this study, we demonstrated the negative regulatory role of RING-finger protein (RNF) 90 in innate immune responses targeting MITA. RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation. Overexpression of RNF90 inhibited HSV-1- or cytosolic DNA-induced immune responses whereas RNF90 knockdown had the opposite effects. Moreover, RNF90-deficient bone marrow-derived dendritic cells (BMDCs), bone marrow-derived macrophages (BMMs) and mouse embryonic fibroblasts (MEFs) exhibited increased DNA virus- or cytosolic DNA-triggered signaling and RNF90 deficiency protected mice from DNA virus infection. Taken together, our findings suggested a novel function of RNF90 in innate immunity. Author summary: After the invasion of viruses, the genetic materials, RNA and DNA generated by the viruses, could be recognized by the cytosolic RNA or DNA sensors and then these sensors will initiate the innate immune signaling pathway and protect the host from viral invasion. However, excessive immune responses may cause tissue damage and do harm to the host. Therefore, the innate immune responses should be tightly controlled and turned off timely. MITA is a key adaptor in DNA-sensor signaling pathway. Here, we find that RNF90, a known E3 ubiquitin-protein ligase, interacted with MITA, enhanced the ubiquitination of MITA and promoted the degradation of MITA. RNF90-defient mice showed increased innate immune responses upon DNA virus HSV-1 infection. Our research revealed a new negative regulatory mechanism of the host to manipulate the antiviral innate immune responses. [ABSTRACT FROM AUTHOR]

Interferon (IFN)‐inducible protein 16 (IFI16) regulates human immunodeficiency virus replication by inducing innate immune responses as a DNA sensor. Human T‐lymphotropic virus type 1 (HTLV‐1), a delta retrovirus family member, has been linked to multiple diseases. Here, we report that IFI16 expression is induced by HTLV‐1 infection or HTLV‐1 reverse transcription intermediate (RTI) ssDNA90 transfection. IFI16 overexpression decreases HTLV‐1 protein expression, whereas IFI16 knockdown increases it. Furthermore, the knockdown of IFI16 is followed by impaired innate immune responses upon HTLV‐1 infection. In addition, IFI16 forms a complex with ssDNA90 and enhances ssDNA90‐triggered innate immune responses. Collectively, our data suggest a critical role for IFI16 during HTLV‐1 infection by interacting with HTLV‐1 RTI ssDNA90 and restricting HTLV‐1 replication. [ABSTRACT FROM AUTHOR]