Chapter 5 : Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection

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This chapter opens with a brief overview of the toll-like receptor (TLR)-dependent and -independent pathways of activation. It then focuses on the activation of transcription factors interferon regulatory factors (IRFs) IRF3 and IRF7 by the atypical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1), and IKK-ε and their role in the induction of type I interferons (IFNs). The majority of IRFs are involved in distinct aspects of the antiviral response, while two members—IRF4 and IRF8—function mainly as regulators of hematopoiesis in concert with the Ets transcription factor. Importantly, expression of the IKK-related kinases is essential to initiate IRF signaling in response to de novo Sendai virus (SeV), vesicular stomatitis virus (VSV), or measles virus infection, and treatment with RNA interference directed against either IKK-ε or TBK1 reduces VSV-inducible IRF3 phosphorylation and IRF-dependent gene expression in human cells. Inhibition of Hsp90 expression by small interfering RNA (siRNA) resulted in an impaired activation of IRF3 following SeV infection. This study proposes that Hsp90 participates in the formation of a complex containing TBK1 and IRF3. In addition to linking TBK1 to the exocyst pathway and Ras-induced transformation, the study demonstrated that the host defense response requires the RalB/Sec5/TBK1 complex following double-stranded RNA (dsRNA) treatment or SeV infection.

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5
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Figure 1

TLR-dependent and -independent sensing of viral infection leads to TBK1/IKK-ε activation. Simplified schematic representation of TLR3, 4, 7/8, and 9 and RIG-I/MDA-5 signaling pathways, leading to TBK1 and IKK-ε activation.

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5
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Image of Figure 2
Figure 2

Schematic representation of IRF7 and IRF5. Schematic diagram of the principal domains of IRF7 (A) and IRF5 (B). The signal response domain is amplified and important amino acids are shown as gray letters with their respective position number. Pro, proline-rich region; PEST, proline-glutamic acid-serine-threonine domain; CAD, constitutive activation domain; VAD, virus-activated domain; P, phosphorylation site.

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5
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Figure 3

Schematic representation of the classical and nonclassical IKK kinases. Shown are schematic diagrams of the principal known domains of IKK-α, IKK-β, TBK1, and IKK-ε. The phosphorylated and ubiquitinated residues are indicated. Sequence homologies of each kinase compared with either IKK-α or IKK-ε are shown as percentages to the right of the schematic. KD, kinase domain; LZ, leucine zipper motif; HLH, helix-loop-helix domain; P, phosphorylation site; Ub, ubiquitination site.

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5
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Figure 4

Adaptor molecules of the IFN signaling pathway. Schematic representation of SINT-BAD, NAP1, TANK, and NEMO adaptor molecules. CC, coiled-coil domain; Pro, proline-rich domain; ZnF, zinc-finger domain; NEMO ID, NEMO interaction domain; TRAF ID, TRAF interaction domain; TANK ID, TANK interaction domain; LZ, leucine zipper motif.

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5
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Figure 5

Negative regulators of the IFN signaling pathway. Schematic representation of A20, SIKE, and DUBA, negative regulators of the IFN pathway. UIM, ubiquitin interacting motif.

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5
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Figure 6

Global overview of the regulation of the RIG-I pathway. Schematic representation of signaling complexes formed after activation of the RIG-I pathway following viral infection. Binding of dsRNA by RIG-I leads to dimerization and exposure of CARD domains, allowing interaction with the CARD domain of MAVS. (Left) The mitochondria adaptor MAVS activates the kinases TBK1/IKK-ε through recruitment of TANK and TRAF3. (Right) The adaptors NAP1 and SINTBAD may form similar complexes with MAVS, the kinases, and TRAF3. Recruitment of TRAF6/2 to MAVS leads to NF-κB activation via RIP-1 and NEMO. Only IKK-ε is recruited directly to the mitochondria. TANK (or NAP1) may dissociate from MAVS and form a large cytoplasmic multimeric complex composed of the classical IKK kinases, NEMO, TBK1/IKK-ε, TRAF3, and RIP-1 (complex I), capable of activating both NF-κB and IRF3/7. K63 linked ubiquitination is shown as arrows with oval dots. Phosphorylation is shown as arrows with round dots. Negative regulators (A20, DUBA, and SIKE) are also shown.

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5
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Table 1

Biological properties of IRF proteins

Citation: Arguello M, Paz S, Hiscott J. 2009. Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection, p 51-74. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch5

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