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  • In the signaling cascade of innate immunity most


    In the signaling cascade of innate immunity, most of the receptor proteins, adaptor proteins, and kinases are modified by ubiquitination to activate and transduce the downstream signaling for efficient production of the IFN and proinflammatory cytokines to combat the pathogens. For example, the K-63 linked ubiquitination of RLRs is essential for their oligomerization and activation [13], [14]. At the meanwhile, after the elimination of the invading microbes, the host ubiquitin conjugating enzyme must shut down the signal transduction properly to prevent the aberrant autoimmunity. In this case, the ubiquitination can negatively regulate the signal transduction by facilitating the degradation of signaling protein. For example, K-48 linked polyubiquitination of RLRs and MAVS by RNF125 lead to their proteasomal-dependent degradation [15]. Therefore, E3 ubiquitin ligases responsible for catalyzing the ubiquitination on their substrates are the major players of accurately initiating and terminating transduction program of innate immunity. In this review, we summarize the E3 ubiquitin ligases, especially the most recently identified, which regulate the function and stability of the key signaling molecules in antiviral innate immunity.
    TLR signaling TLRs are type I transmembrane domain proteins with a tripartite structure: an N-terminal extracellular domain essential for ligand recognition, a single transmembrane spanning region, and a cytoplasmic C-terminal globular Toll/interleukin-1 (IL-1) receptor (TIR) domain accountable for signal transduction [16]. TLR3, TLR7, TLR8, and TLR9 are responsible for sensing endosomal nucleic acids derived from the enclosed microbes. TLR3 and TLR7/8 recognize dsRNA and ssRNA, respectively. For TLR9, it detects unmethylated CpG DNA species [17]. The TLRs employ their TIR domain to interact with two adaptor proteins, TRIF and MyD88, to relay the distinct downstream signaling. TRIF interacts with TLR3, whereas MyD88 binds with TLR7/8/9. In TLR3-TRIF pathway, TRIF associates with the ubiquitin E3 ligase Tumor Necrosis Factor (TNF) receptor-associated factor 3 (TRAF3) to activate TBK1 and IKKε [18]. Activated TBK1 and IKKε then phosphorylate IRF3 to drive the expression of type I IFN [7]. On the other hand, TRIF also interacts with TRAF6 and Receptor-interacting serine/threonine-protein kinase 1 (RIP1) [19], leading to the activation of TGF-β-activated kinase 1 (TAK1) and subsequent IKK complex. The activation of classical IKK complex, as aforementioned, can phosphorylate IκBα and lead to its proteasome-dependent degradation. Therefore the sequestered NF-κB is liberated from the cytoplasm and translocated to the nucleus [20]. MyD88-dependent TLR pathways typically are engaged in leading to the production of proinflammatory cytokines. Recruitment of downstream molecules such as kinases interleukin-1 receptor-associated kinase 4 (IRAK4), IRAK1, and ubiquitin ligase TRAF6 by MyD88 results in the activation of TAK1 [20]. Upon activation, TAK1 phosphorylates IKKβ in the classical IKK complex, which ultimately causes the activation of NF-κB and subsequent expression of proinflammatory cytokines such as TNF, interleukin 6 (IL-6), and IL-12.
    RLR signaling of RNA virus RLRs, a family of DExD/H-box RNA helicases, participate in the recognition of viral RNA species in the cytosol of infected cells. The two well-characterized RLR members are retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), both of which harbor two tandem N-terminal caspase activation and recruitment domains (CARDs), a central helicase domain, and a C-terminal domain (CTD) [28]. CARD domain is critical for transducing downstream signaling, while helicase domain and CTD are responsible for binding with RNA. RIG-I and MDA5 detect different RNA species. RIG-I can detect 5\' triphosphorylated ssRNA, short dsRNA, whereas MDA5 is accountable for recognition of long dsRNA [29]. The in vivo functional studies have suggested that RIG-I is essential for sensing of RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus, whereas MDA5 is indispensable for picornavirus detection [30]. The third RLR member LGP2 (laboratory of genetics and physiology 2), lacking the CARD domain critical for activation of downstream signaling, was suggested to be a physiological negative feedback regulator [31]. But a recent study suggests that LGP2 may play a positive role through regulating MDA5-RNA interaction [32].