RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation

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. OPEN ACCESS Citation: Yang B, Liu Y, Cui Y, Song D, Zhang G, Ma S, et al. (2020) RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation. PLoS Pathog 16(3): e1008387.

TRIM Proteins in Host Defense and Viral Pathogenesis

“…3c #6 ) and in IFN induction [ 135 ••], which is also in line with our own findings that TRIM7 KO cells have reduced IFNβ induction upon ZIKV infection or PRR stimulation, the data from in vivo infections in Trim7 −/− mice suggest that the pro-viral roles of TRIM7 are dominant over its potential IFN-mediated antiviral roles in specific cell types and in vivo [ 17 ••]. In addition, TRIM7 was also recently described to negatively regulate responses to DNA viruses by targeting STING for degradation [ 136 •] (Fig. 3c #5 ), so TRIM7 could also play a role in alternative innate immune signaling pathways during ZIKV infection, especially if DNA damage occurs during virus infection that could lead to activation of the cGAS-STING pathway.…”

Crystal structure and mutational analysis of the human TRIM7 B30.2 domain provide insights into the molecular basis of its binding to glycogenin-1

“…In addition to enhancing the activity of GN1, TRIM7 has E3 ubiquitin ligase activity ( 14 ), and through this function, it participates in several processes including glycogen accumulation ( 20 ), cancer development ( 14 , 15 , 16 , 17 ), regulation of atherosclerosis ( 18 ), and of the toll-like receptor 4–mediated innate response ( 23 ). The E3 ubiquitin ligase function is also involved in the immune response against viral infections ( 20 , 21 , 22 ).…”

“…It is therefore conceivable that in addition to interacting with GN1 and Src, TRIM7 B30.2 also participates in the interaction with other proteins and in this way mediates the different effects related to TRIM7. Among these proteins are probably RACO-1 ( 14 ), dual specificity phosphatase 6 ( 15 ), breast cancer metastasis suppressor 1 ( 17 ), the envelope protein of Zika virus ( 20 ), and mediator of IRF3 activation ( 22 ), all of them targets of TRIM7-mediated ubiquitination. Moreover, increased levels of TRIM7 correlate with the size of lung and liver tumors; interestingly, according to the Catalogue of Somatic Mutations in Cancer database of tumors from cancer patients ( 44 ), approximately 54% of the mutations associated with the TRIM7 gene are located in the B30.2 domain ( Fig.…”

“…Recent studies have also revealed that TRIM7 ubiquitinates Zika virus envelope protein, thereby favoring the entry of the virus into host cells and pathogenesis ( 20 ). Moreover, TRIM7 has been shown to inhibit norovirus infection in human cells ( 21 ) and the innate immune response against DNA virus through mediator of IRF3 activation ubiquitination and proteasome-mediated degradation ( 22 ). In addition, TRIM7 has an activating effect on the immune response mediated by Toll-like receptor 4 in macrophages ( 23 ).…”

The E3 Ubiquitin Ligase RNF5 Facilitates SARS-CoV-2 Membrane Protein-Mediated Virion Release

“…RING finger protein family (RNF) have been demonstrated in the regulation of antiviral responses. RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1 (24), RNF90 negatively regulates cellular antiviral responses by targeting MITA for degradation (25), RNF11 targets TBK1/IKKi kinases to inhibit antiviral signaling (26). RNF5, also known as RMA1, is a RING finger protein and a membrane-anchored (ER and/or mitochondria) E3 ubiquitin ligase, which anchored to the ER membrane via a single transmembrane, spanning the domain located within the C-terminal region.…”