Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense.
The rapid induction of type I IFN is a central event of the innate defense against viral infections and is tightly regulated by a number of cellular molecules. Viral components induce strong type I IFN responses through the activation of toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as an RNA helicase RIG-I and/or MDA5. According to recent studies, the NF-kappaB essential modulator (NEMO, also called IKKgamma) is crucial for this virus-induced antiviral response. However, the precise roles of signal activation by NEMO adaptor have not been elucidated. Here, we show that virus-induced IRF3 and NF-kappaB activation depends on the K(lys)-27-linked polyubiquitination to NEMO by the novel ubiquitin E3 ligase triparite motif protein 23 (TRIM23). Virus-induced IRF3 and NF-kappaB activation, as well as K27-linked NEMO polyubiquitination, were abrogated in TRIM23 knockdown cells, whereas TRIM23 knockdown had no effect on TNFalpha-mediated NF-kappaB activation. Furthermore, in NEMO-deficient mouse embryo fibroblast cells, IFN-stimulated response element-driven reporter activity was restored by ectopic expression of WT NEMO, as expected, but only partial recovery by NEMO K165/309/325/326/344R multipoints mutant on which TRIM23-mediated ubiquitin conjugation was substantially reduced. Thus, we conclude that TRIM23-mediated ubiquitin conjugation to NEMO is essential for TLR3- and RIG-I/MDA5-mediated antiviral innate and inflammatory responses.
Arimoto
Kei-ichiro
K
Institute for Virus Research, Kyoto University, Shogo-in, Sakyo-ku, Japan.
Funami
Kenji
K
Saeki
Yasushi
Y
Tanaka
Keiji
K
Okawa
Katsuya
K
Takeuchi
Osamu
O
Akira
Shizuo
S
Murakami
Yoshiki
Y
Shimotohno
Kunitada
K
D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism*
C491731:IKBKG protein, human; C080681:TRIM23 protein, human; D025821:Polyubiquitin; D051550:I-kappa B Kinase; D019204:GTP-Binding Proteins