Crystal structure of human IRAK1

Wang, Li; Qiao, Qi; Ferrao, Ryan; Shen, Chen; Hatcher, John M.; Buhrlage, Sara J.; Gray, Nathanael S.; Wu, Hao

doi:10.1073/pnas.1714386114

Cited by 65 publications

(93 citation statements)

References 41 publications

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“…It has not proved possible to over-express full-length IRAK1 and TRAF6 in E. coli, although various sub-domains of these proteins have been successfully produced (Fu et al 2018;Ye et al 2002;Wang et al 2017). This is most likely because both enzymes are multi-domain human proteins, most of which are notoriously recalcitrant to expression in recombinant bacteria.…”

Section: Resultsmentioning

confidence: 99%

“…Toll-like receptor 7 (TLR7) and TLR9 are among various pattern recognition receptors that sense viral nucleic acids and induce production of type I interferons by plasmacytoid dendritic cells (pDCs) to protect the host from viral infection (Wu and Chen 2014). As a component of this pathway, viperin stimulates the K63-linked polyubiquitination of interleukin-1 receptor-associated kinase (IRAK1) (Wang et al 2017;Conze et al 2008;Honda et al 2004) by the E3 ubiquitin ligase, TRAF6 (Saitoh et al 2011;Conze et al 2008). K63-linked poly-ubiquitination, in turn, activates IRAK1 to phosphorylate interferon regulatory factor 7 (IRF7), causing IRF7 to migrate to the nucleus where it activates transcription of type 1 interferons (Honda et al 2004;Honda et al 2006) (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Interactions between Viperin, IRAK1 andTRAF6 couple innate immune signaling to antiviral ribonucleotide synthesis

Dumbrepatil

Ghosh

Patel

et al. 2018

Preprint

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Viperin is a radical S-adenosylmethionine (SAM) enzyme that plays a multifaceted role in the cellular antiviral response. Viperin was recently shown to catalyze the SAM-dependent formation of 3ʹ-deoxy-3′,4ʹ-didehydro-CTP (ddhCTP), which inhibits some viral RNA polymerases. Viperin is also implicated in regulating K63-linked poly-ubiquitination of interleukin-1 receptor-associated kinase-1 (IRAK1) by the E3 ubiquitin ligase TNF Receptor-Associated Factor 6 (TRAF6) as part of the Toll-like receptor-7 and 9 (TLR7/9) innate immune signaling pathways. We show that IRAK1 and TRAF6 activate viperin to efficiently catalyze the radical-mediated dehydration of CTP to ddhCTP. Furthermore, poly-ubiquitination of IRAK1 requires the association of viperin with IRAK1 and TRAF6. Poly-ubiquitination appears dependent on structural changes induced by SAM binding to viperin but does not require catalytically active viperin. The synergistic activation of viperin and IRAK1 provides a mechanism that couples innate immune signaling with the production of the antiviral nucleotide ddhCTP.that viperin catalyzes the formation of a novel antiviral ribonucleotide, 3ʹ-deoxy-3',4ʹ-didehydro-CTP (ddhCTP; Fig 1d) and that overexpression of viperin in HEK293 causes significant levels of ddhCTP to accumulate (Gizzi et al. 2018). ddhCTP is formed by the dehydration of CTP in a SAM-dependent reaction that is initiated by abstraction of the 4'-hydrogen by the 5'deoxyadenosyl radical. ddhCTP was shown to be an effective chain-terminating inhibitor of RNA synthesis by viral RNA-dependent RNA polymerases from flaviviruses including dengue virus, west Nile virus and Zika virus, thereby providing an explanation for viperin's antiviral properties (Gizzi et al. 2018). The production of anti-viral nucleotides provides one explanation for viperin's antiviral properties; however, many aspects of the enzyme's antiviral effects are not readily explained by the production of ddhCTP. For example, it appears that catalytically inactive viperin mutants are still capable of restricting influenza A infection (Vonderstein et al. 2017), and ddhCTP was designed the experiments. A.B.D. and E.N.G.M. wrote the paper.hepatitis C virus replication by interfering with binding of NS5A to host protein hVAP-33', J Gen Virol, 93: 83-92. Wang, X., E. R. Hinson, and P. Cresswell. 2007. 'The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts', Cell Host Microbe, 2: 96-105. Wu, J. X., and Z. . 2002. 'Distinct molecular mechanism for initiating TRAF6 signalling', Nature, 418: 443-47.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interactions between Viperin, IRAK1 andTRAF6 couple innate immune signaling to antiviral ribonucleotide synthesis

Dumbrepatil

Ghosh

Patel

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…41 IRAK1 belongs to a family of serine/threonine kinases and plays a vital role in the immune response by serving as a key molecule in the Toll-like receptor signaling pathway. 42 TRAF6 is identified as an actor downstream of multiple receptor families, including the Toll-like receptor signaling pathway, and can promote the activation of the transcription factor NF-κB. 43 Based on current research, SMAD4, TRAF6, and IRAK1 are all predominantly enriched in the inflammatory signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

<p>Long Non-Coding RNAs Regulate Inflammation in Diabetic Peripheral Neuropathy by Acting as ceRNAs Targeting miR-146a-5p</p>

Feng

et al. 2020

DMSO

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Background: Long non-coding RNAs (lncRNAs), as competing endogenous RNAs (ceRNAs), can regulate various pathophysiological processes by binding competitively to microRNAs at the post-transcription level. Our previous work demonstrated that miR-146a-5p was lowly expressed in diabetic peripheral neuropathy (DPN) rats. However, the ceRNA network in DPN mediated by lncRNAs and miR-146a-5p remains to be explored. Methods: Two groups of rats (n=4 per group), a type 2 diabetes (T2DM) group and a DPN group, were used in this study. Sciatic nerve conduction velocity (NCV) of each rat was determined at the 6th and the 12th week. LncRNA microarray analysis was performed in the sciatic nerve of DPN and T2DM rats. Based on the TargetScan algorithm and the miRanda database, we determined the differentially expressed (DE) lncRNAs bound to miR-146a-5p. Furthermore, we verified the DE lncRNAs potentially bound to miR-146a-5p by qRT-PCR. The genes targeted by miR-146a-5p were identified by bioinformatics prediction and experimental techniques. Results: We found 413 DE lncRNAs between DPN and T2DM rats (|log2FC| ≥ 2 and adjust P ≤ 0.05). Eight DE lncRNAs were predicted to bind to miR-146a-5p by both algorithms, of which four were verified by qRT-PCR. TRAF6, IRAK1, and SMAD4 were identified as miR-146a-5p targeted genes and were predominantly enriched in the inflammatory signaling pathway. Conclusion: LncRNAs may contribute to the pathogenesis of DPN by regulating inflammation through functioning as ceRNAs of miR-146a-5p.

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“…The MyD88-dependent pathway is activated by the TLR4 ligand LPS. Upon ligand binding, TLRs recruit adaptor proteins MyD88, activating the IRAK1 and IRAK4, enabling the recruitment of TNF receptor-associated factor 6 (TRAF6), which phosphorylates transforming growth factor-b-activated kinase 1 binding protein 2/3 (TAB2/TAB3) and transforming growth factor-b-activated kinase 1 (TAK1), leading to the activation of the NF-kB and MAPK signaling pathway (Ajibade et al, 2013;Wang et al, 2017). Our data showed that GH downregulated the activation of TLR4-MyD88 signaling pathway in RAW 264.7 cells and BMDMs.…”

Section: Discussionmentioning

confidence: 99%

Gaudichaudione H Inhibits Inflammatory Responses in Macrophages and Dextran Sodium Sulfate-Induced Colitis in Mice

Jiang

Xiao

et al. 2020

Front. Pharmacol.

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Macrophages-involved inflammation is considered to induce the damage in various diseases. Herein, novel therapeutics inhibiting over-activation of macrophages could prove an effective strategy to prevent inflammation-related diseases. Gaudichaudione H (GH), which is a natural small molecular compound isolated from Garcinia oligantha Merr. (Clusiaceae) has previously been demonstrated its anti-cancer effects on several cancer cell lines. However, no report has been published about the anti-inflammatory effect of GH to date. This study aims to examine the anti-inflammatory effects and potential molecular mechanism of GH, and provide new insights toward the treatment of inflammation. GH inhibited nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, cytokine interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) production, and messenger RNA (mRNA) expression to attenuate inflammatory responses in lipopolysaccharide (LPS)-induced RAW 264.7 cells or stimulated bone marrow-derived macrophages (BMDMs). GH inhibited nuclear factor-kB (NF-kB) and mitogen-activated protein kinase (MAPK) pathways, the nuclear translocation of transcription factors NF-kB and activator protein 1 (AP-1), as well as upstream signaling of the toll-like receptor 4 (TLR4)-myeloid differentiation primary response 88 (MyD88) pathway in stimulated macrophages. Furthermore, the result of the intracellular signaling array showed that the phosphorylation of adenosine 5'monophosphate-activated protein kinase-a (AMPKa), proline-rich Akt substrate of 40 kDa (PRAS40), and p38 could be down regulated by GH in BMDMs, indicating that the mechanism by which GH inhibited inflammation may be also associated with the energy metabolism pathway, PRAS40-mediated NF-kB pathway, cell proliferation, apoptosis, and autophagy, etc. In addition, GH alleviated dextran sodium sulfate (DSS)-induced colitis in mice by ameliorating weight loss, stool consistency change, blood in the stool, and colon shortening. GH decreased the protein and mRNA levels of IL-6 and TNF-a, iNOS and COX-2 mRNA expression, the activation of NF-kB and MAPK pathways, the phosphorylation of AMPKa and PRAS40, histological damage, and infiltration of macrophages in the colons of mice with DSS-induced colitis. Taken together, our

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Crystal structure of human IRAK1

Cited by 65 publications

References 41 publications

Interactions between Viperin, IRAK1 andTRAF6 couple innate immune signaling to antiviral ribonucleotide synthesis

Interactions between Viperin, IRAK1 andTRAF6 couple innate immune signaling to antiviral ribonucleotide synthesis

<p>Long Non-Coding RNAs Regulate Inflammation in Diabetic Peripheral Neuropathy by Acting as ceRNAs Targeting miR-146a-5p</p>

Gaudichaudione H Inhibits Inflammatory Responses in Macrophages and Dextran Sodium Sulfate-Induced Colitis in Mice

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