| First Author | Smith H | Year | 2011 |
| Journal | Biochem J | Volume | 434 |
| Issue | 3 | Pages | 537-48 |
| PubMed ID | 21204785 | Mgi Jnum | J:169474 |
| Mgi Id | MGI:4941089 | Doi | 10.1042/BJ20101421 |
| Citation | Smith H, et al. (2011) The role of TBK1 and IKK in the expression and activation of Pellino 1. Biochem J 434(3):537-48 |
| abstractText | Mammalian Pellino isoforms are phosphorylated by IRAK (interleukin receptor associated kinase) 1/IRAK4 in vitro, converting them into active E3 ubiquitin ligases. In the present paper we report a striking enhancement in both transcription of the gene encoding Pellino 1 and Pellino 1 protein expression when murine BMDMs (bone-marrow-derived macrophages) are stimulated with LPS (lipopolysaccharide) or poly(I:C). This induction occurs via a TRIF [TIR (Toll/interleukin-1 receptor)-domain-containing adaptor-inducing interferon-beta]-dependent IRAK-independent pathway and is prevented by inhibition of the IKK [IkappaB (inhibitor of nuclear factor kappaB) kinase]-related protein kinases, TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor kappaB activator]-binding kinase 1} and IKK. Pellino 1 is not induced in IRF3 (interferon regulatory factor 3)-/- BMDMs, and its induction is only reduced slightly in type 1 interferon receptor-/- BMDMs, identifying Pellino 1 as a new IRF3-dependent gene. We also identify Pellino 1 in a two-hybrid screen using IKK as bait, and show that IKK/TBK1 activate Pellino 1 in vitro by phosphorylating Ser76, Thr288 and Ser293. Moreover, we show that the E3 ligase activity of endogenous Pellino 1 is activated in LPS- or poly(I:C)-stimulated macrophages. This occurs more rapidly than the increase in Pellino 1 mRNA and protein expression, is prevented by the inhibition of IKK/TBK1 and is reversed by phosphatase treatment. Thus IKK/TBK1 mediate the activation of Pellino 1's E3 ligase activity, as well as inducing the transcription of its gene and protein expression in response to TLR3 and TLR4 agonists. |
