RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation
PLOS PATHOGENS(2020)
Abstract
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.
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