A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKγ to dampen the host NF-κB-mediated inflammatory response

Ashida, Hiroshi; Kim, Minsoo; Schmidt-Supprian, Marc; Ma, Averil; Ogawa, Michinaga; Sasakawa, Chihiro

doi:10.1038/ncb2006

Cited by 224 publications

(203 citation statements)

References 34 publications

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“…Moreover, recently, it was reported that bacterial E3 ligase IpaH9.8 promotes K27-linked ubiquitin conjugation to NEMO and facilitates degradation of NEMO with unidentified molecule(s) activated by NOD1 signaling (37). Although both E3 ligases, TRIM23, and bacterially encoded IpaH9.8 conjugate K27-linked ubiquitin to NEMO, the outcomes are totally different.…”

Section: Discussionmentioning

confidence: 96%

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

Arimoto

Funami

Saeki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

148

124

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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-κB essential modulator (NEMO, also called IKKγ) 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-κB 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-κB activation, as well as K27-linked NEMO polyubiquitination, were abrogated in TRIM23 knockdown cells, whereas TRIM23 knockdown had no effect on TNFα-mediated NF-κB 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.innate immunity | signal transduction | virus infection U pon viral infection, host cells recognize the viral components and activate innate immune signaling to exert antiviral responses (1-4). RIG-I and/or MDA5 sense viral dsRNA (5-8) and are recruited to another antiviral signaling adaptor, IPS-1 (also called MAVS, Cardif, or VISA) (9-12). IPS-1 directly interacts with TRAF3 and triggers auto-ubiquitination of TRAF3, which then activates TBK1 and IKKε, leading to activation of transcription factors NF-κB and IRF3 (13,14). A recent study indicated that NEMO acts upstream of TBK1 and IKKε and is essential for virus-induced TLR3-and RIG-I/MDA5-mediated antiviral activation (15).Because rapid induction of type I IFN expression is the key process in initiating the innate antiviral response, clarification of NEMO-mediated antiviral signaling is important for understanding innate immune signaling; however, NEMO-mediated antiviral signaling is not well elucidated. Recent studies indicate that several ubiquitin E3 ligases are involved in the regulation of innate immune signaling (16-21). We identified the ubiquitin E3 ligase TRIM23 (Triparite motif protein 23), also named ADP ribosylation factor domain protein 1 (ARD1), which was reported to have E3 ligase activity in vitro (22), that functioned as an E3 ligase for NEMO ubiquitin conjugation. TRIM23 exerts a potent antiviral state following its overexpression. Furthermore, we demonstrated that antiviral activity depends not on K(Lys)63-linked but on K27-linked polyubiquitin conjugation to multiple sites of NEMO by TRIM23 expression. Virus-in...

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Section: Discussionmentioning

confidence: 96%

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

Arimoto

Funami

Saeki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

148

124

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“…Enteropathogenic Escherichia coli (EPEC) also has been shown to prevent the phosphorylation of IκB through the use of two T3SS effectors, NleE and NleB, which interact with the TAK1-IKK A B pathway, albeit in an unknown fashion (38). Finally, Shigella has at least two effectors, OspG and IpaH9.8, that interfere with the NF-κB pathway (25,39). IpaH9.8 is an ubiquitin ligase that interacts and interferes with NEMO, thereby impairing IκB phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting the IκB kinase subunit IKKα

Gouin

Adib‐Conquy

Balestrino

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Listeria monocytogenes is an intracellular pathogen responsible for severe foodborne infections. It can replicate in both phagocytic and nonphagocytic mammalian cells. The infectious process at the cellular level has been studied extensively, but how the bacterium overcomes early host innate immune responses remains largely unknown. Here we show that InlC, a member of the internalin family, is secreted intracellularly and directly interacts with IKKα, a subunit of the IκB kinase complex critical for the phosphorylation of IκB and activation of NF-κB, the major regulator of innate immune responses. Infection experiments with WT Listeria or the inlC-deletion mutant and transfection of cells with InlC reveal that InlC expression impairs phosphorylation and consequently delays IκB degradation normally induced by TNF-α, a classical NF-κB stimulator. Moreover, infection of RAW 264.7 macrophages by the inlC mutant leads to increased production of proinflammatory cytokines compared with that obtained with the WT. Finally, in a peritonitis mouse model, we show that infection with the inlC mutant induces increased production of chemokines and increased recruitment of neutrophils in the peritoneal cavity compared with infection with WT. Together, these results demonstrate that InlC, by interacting with IKKα, dampens the host innate response induced by Listeria during the infection process.anti-inflammation | NF-κB | virulence | cytokines | internalin T he Gram-positive bacterium Listeria monocytogenes infects human and animal hosts and causes foodborne infections that can lead to bacteremia and meningitis. It mainly affects immunocompromised patients, pregnant women, and newborns. Once inside the host, L. monocytogenes can invade both phagocytic and nonphagocytic cell types, replicate intracellularly, and spread directly from cell to cell, thereby escaping the humoral immune response. The successive steps of this intracellular parasitism are dependent on various virulence factors, including the surface proteins InlA and InlB, required for entry into cells; secreted proteins listeriolysin O (LLO) and phospholipases, involved in escape from the primary and secondary vacuoles; and ActA, responsible for actin-based intracellular and intercellular movements. These virulence factors are positively controlled by the transcriptional activator PrfA (1-3).The complete genome sequence of L. monocytogenes strain EGD-e has revealed the presence of 25 genes encoding proteins of the internalin family (4-6). Proteins of this family are characterized by the presence of a leucine-rich repeat (LRR) domain. Most of these are surface proteins attached to the bacterial surface by different anchoring motifs, in particular the LPXTG motif, which mediates covalent binding to the peptidoglycan. Some of these internalin proteins are well-characterized virulence factors, including internalin A (InlA, the prototype of the family) and InlB, which are involved in the crossing of intestinal and placental barriers (7, 8). Only four proteins of the interna...

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“…102 Certain NEL family members, including IpaH9.8, IpaH0722 and IpaH4.5, have been shown to tamper with the host NF-κB cascade by ubiquitinating NEMO, TRAF2 and p65 for proteasomal degradation, respectively. [103][104][105] Another NEL effector, IpaH7.8, possesses E3 ligase activity in vitro and targets an inhibitor of Cullin-based RING E3 ligase named GLMN for degradation, which augments inflammasome activation. 106 In addition, OspG and OspI, belonging to a different subsets of S. flexneri effectors, have recently been identified to suppress NF-κB activation by disrupting the ubiquitin system.…”

Section: Shigella Flexnerimentioning

confidence: 99%

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

Chai

Liu

2016

Cell Mol Immunol

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The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.

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A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKγ to dampen the host NF-κB-mediated inflammatory response

Cited by 224 publications

References 34 publications

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting the IκB kinase subunit IKKα

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

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