Abstract
Viral infection triggers induction of type I interferons (IFNs), which are critical mediators of innate antiviral immune response. Mediator of IRF3 activation (MITA, also called STING) is an adapter essential for virus-triggered IFN induction pathways. How post-translational modifications regulate the activity of MITA is not fully elucidated. In expression screens, we identified RING finger protein 26 (RNF26), an E3 ubiquitin ligase, could mediate polyubiquitination of MITA. Interestingly, RNF26 promoted K11-linked polyubiquitination of MITA at lysine 150, a residue also targeted by RNF5 for K48-linked polyubiquitination. Further experiments indicated that RNF26 protected MITA from RNF5-mediated K48-linked polyubiquitination and degradation that was required for quick and efficient type I IFN and proinflammatory cytokine induction after viral infection. On the other hand, RNF26 was required to limit excessive type I IFN response but not proinflammatory cytokine induction by promoting autophagic degradation of IRF3. Consistently, knockdown of RNF26 inhibited the expression of IFNB1 gene in various cells at the early phase and promoted it at the late phase of viral infection, respectively. Furthermore, knockdown of RNF26 inhibited viral replication, indicating that RNF26 antagonizes cellular antiviral response. Our findings thus suggest that RNF26 temporally regulates innate antiviral response by two distinct mechanisms.
Highlights
Host pattern-recognition receptors (PRRs) detect nucleic acid from invading viruses or necrotic cells and trigger a series of signaling events that lead to the induction of type I interferons (IFNs), which plays a central role in autoimmune diseases as well as protective immune responses against viruses, respectively [1,2]
A family of DExD/H box RNA helicases consisting of retinoic acid inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and LGP2 are RNA sensors and recruit the adaptors VISA [3,4,5,6] and MITA [7,8,9,10]to activate the transcription factors NF-kB and interferon regulatory factor (IRF) 3 or IRF7, leading to transcriptional induction of the genes encoding type I IFNs and other antiviral effectors [2]
Consistent with the gene induction experiments, we found that SeV- or HSV-1-induced phosphorylation of TBK1 and IkBa was inhibited in THP-1-RING finger protein 26 (RNF26)-RNAi cells, phosphorylation of IRF3 was inhibited at the early time points and increased at the late time points in THP-1-RNF26-RNAi stable cells compared to that in control cells after viral infection (Figure 6G)
Summary
Host pattern-recognition receptors (PRRs) detect nucleic acid from invading viruses or necrotic cells and trigger a series of signaling events that lead to the induction of type I interferons (IFNs), which plays a central role in autoimmune diseases as well as protective immune responses against viruses, respectively [1,2]. Cyclic GMP-AMP synthase (cGAS) has been recently characterized as a viral DNA sensor in almost all types of cells [15]. These sensors depend exclusively on the adaptor MITA to activate NF-kB and IRF3/7 and lead to subsequent induction of type I IFNs [16]
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