Ubiquitin in the activation and attenuation of innate antiviral immunity

Heaton, Steven M.; Borg, Natalie A.; Dixit, Vishva M.

TLRs are differentially expressed in a wide range of cell populations. TLR3, TLR7, TLR8, and TLR9 are expressed in endosomal vesicles, whereas TLR2 and TLR4 are expressed on the cell surface. TLR3 recognizes double-stranded RNA, activating NF-κB-mediated proinflammatory cytokine production and strongly up-regulating TBK1/IRF3-dependent IFN-I expression. TLR7 and TLR8 recognize ssRNA, up-regulating IFN-α and proinflammatory cytokine production. TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) DNA, a common feature of nonmammalian genomes, and stimulates IFN-α production. TLR2 and TLR4 are activated by a variety of microbial ligands, including specific viral proteins, resulting in proinflammatory cytokine expression (Fig. 2, left) . NF-κB activation and IFN-I up-regulation. TLR2, TLR4, TLR7, TLR8, and TLR9 signaling is mediated through the adaptor protein myeloid differentiation primary response gene 88 (MyD88; Fig. 2 , left). MyD88 recruits NF-κB and IFN-I signaling components, including interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TRAF6, and IRF7. Activated TRAF6 ubiquitinates IRF7, leading to IFN-α expression (Kawai et al., 2004) . TRAF6 also promotes K63linked polyubiquitination of NEMO, enabling recruitment of the TGF-β-activated kinase (TAB)-TAK1 kinase complex (Tseng et al., 2010) . Subsequent association between NEMO and M1-polyubiquitin chains induces TAK1-mediated phosphorylation of IKKα and IKKβ, priming them for full transactivation through autophosphorylation . Activated IKKα phosphorylates the IκBα subunit, leading to its ubiquitination and proteasomal degradation and releasing NF-κB for nuclear translocation. Furthermore, MyD88, IRAK1/4, and TAB2/3 are also modified and activated by K63-linked polyubiquitin chains. Such chains were recently described as substrates for M1-polyubiquitination by HOIP, resulting in hybrid chains that may connect the MyD88/ IRAK and TAK1/IKK signaling apparatus (Emmerich et al., 2013) . TLR3 signaling is mediated by TIR domain-containing adaptor-inducing IFN-β (TRIF). TRIF activates TRAF3, which promotes IRF3/IRF7 activation (Tseng et al., 2010) , and also TRAF6, which promotes IKK activation (Fig. 2, left; Jiang et al., 2004) .