The TAK1-JNK cascade is required for IRF3 function in the innate immune response

Abstract

Interferon regulatory factor (IRF)3 is critical for the transcriptional induction of chemokines and cytokines during viral or bacterial invasion. The kinases Tank binding kinase (TBK)1 and Ikappa B kinase (IKK)ε can phosphorylate the C-terminal part of IRF3 and play important roles in IRF3 activation. In this study, we show that another kinase, c-Jun-NH 2 -terminal kinase (JNK), phosphorylates IRF3 on its N-terminal serine 173 residue, and TAK1 can stimulate IRF3 phosphorylation via JNK. JNK specific inhibitor SP600125 inhibits the N-terminal phosphorylation without affecting the C-terminal phosphorylation. In addition, IRF3-mediated gene expressions on lipopolysaccharide (LPS) or polyinosinic-cytidylic acid (polyI:C) treatment are severely impaired by SP600125, as well as for reporter gene assay of IRF3 activation. Knockdown of TAK1 further confirmed these observations. Interestingly, constitutive active IRF3(5D) can be inhibited by SP600125; JNK1 can synergize the action of IRF3(5D), but not the S173A-IRF3(5D) mutant. More importantly, polyI:C failed to induce the phosphorylation of mutant S173A and SP600125 dramatically abrogated IRF3 phosphorylation and dimerization that was stimulated by polyI:C. Thus, this study demonstrates that the TAK1-JNK cascade is required for IRF3 function, in addition to TBK1/IKKε, uncovering a new mechanism for mitogen-activated protein (MAP) kinase to regulate the innate immunity.

Human T Cell Lymphotropic Virus 1 Manipulates Interferon Regulatory Signals by Controlling the TAK1-IRF3 and IRF4 Pathways

“…It has recently been reported that Tax interferes with the IFN-␣-induced JAK-STAT pathway by competition with STAT2 for CBP/p300 binding (25), suggesting that Tax controls two different IFN signaling pathways. In addition, the TAK1-JNK cascade is required for IRF3 function in macrophages (18). In contrast, the RNAi experiment ruled out JNK and p38 in IRF3 phosphorylation in HuT-102 cells (data not shown).…”

“…TAK1 is known as a key kinase leading to NF-B in tumor necrosis factor-␣ and interleukin-1 signaling pathways (14,15); however, it is dispensable in Tax-dependent constitutive NF-B activation (13). TAK1 has been demonstrated to participate in TLR-mediated activation of NF-B (16) but not the TBK1-IRF3/7 pathway (17,18); however, the role of constitutive TAK1 activation in IFN-regulatory signals triggered by HTLV-1 is still largely unknown.…”

Listeria monocytogenes Strain-Specific Impairment of the TetR Regulator Underlies the Drastic Increase in Cyclic di-AMP Secretion and Beta Interferon-Inducing Ability

“…These data clearly showed that LO28 has a distinct ability for IFN-␤ induction compared to EGD. Recent reports have shown that IRF3 plays an essential role in the expression of IFN-␤, and TBK1 and JNK contribute to the activation of IRF3 through phosphorylation of IRF3 at the C terminus and N terminus, respectively (39,54). We thus determined whether the activation of these transcription factors is associated with the increased production of IFN-␤ in LO28-infected macrophages.…”

A Novel IRAK1–IKKε Signaling Axis Limits the Activation of TAK1–IKKβ Downstream of TLR3

“…Furthermore, JNK was shown to be involved in the phosphorylation of IRF3 (Ser 173 ), acting as a positive regulator of IRF3 activation (28). Therefore, we addressed whether IRAK1 and IKKε had a functional role in MAPK activation downstream of TLR3, as assessed by Western blot analysis (Fig.…”