The Roles of TRAF3 in Immune Responses

Lin, Mengjiao; Ji, Xiaoli; Lv, Yan; Cui, Dawei

doi:10.1155/2023/7787803

Cited by 19 publications

(11 citation statements)

References 111 publications

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“…Another MAP3K lying downstream of TRAF6 that activates NF-κB is MEKK3 (Qin et al 2006; Yao et al 2007; Fraczek et al 2008). Likewise, TLR3 (and also some TLR4) through interacting with the cytosolic TRIF adaptor associates with TRAF3, which auto-ubiquitinates itself with K63-linked polyubiquitin chains recruiting atypical IKK members TBK1 and IKKε (Hacker, Tseng, and Karin 2011; Lin et al 2023). TBK1 and IKKε upon autophosphorylation phosphoactivate the transcription factor IRF3, resulting in the induction of Type I interferon response (Hemmi et al 2004; Perry et al 2004; Shu et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

Chan,

Sun,

Bhushan

et al. 2023

Preprint

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The corneal epithelium at the ocular surface is constantly exposed to the environment and represents the first line of defense against infection, mechanical injury or chemical irritation. Through TLR-mediated recognition of pathogen- and damage-associated molecular patterns, it engages in direct antimicrobial responses and alerts the immune system on intruder and tissue damage by secreting pro-inflammatory and chemotactic cytokines that promote immune cell infiltration. How the corneal epithelium downregulates TLR signaling is unclear, yet it highly expresses keratin 6a (K6a), a cytoskeletal protein that has emerged to play essential regulatory roles in corneal innate immune response. Here we report that mice harboring genetic deletion of K6a are more susceptible to developing bacterial keratitis with unresolved corneal opacification and higher bacterial load. Such disease phenotype is caused by the increased pro-inflammatory cytokine and chemokine secretions from the K6a-null corneal epithelium, which further promotes the infiltration of immune cells and their associated pro-inflammatory response. Using human corneal epithelial cells immortalized by telomerase reverse transcriptase (hTCEpi cells), we demonstrated that knocking down K6a enhances NF-κB/ RelA-dependent cytokine and chemokine expression. Moreover, proteomic screen reveals that K6a interacts with ELKS, a critical NEMO-binding scaffold that links between canonical IKKα/β and the principal cytoplasmic inhibitor of RelA, i.e. IκBα., to promote its phosphorylation and degradation. Surprisingly, K6a does not antagonize any of these canonical NF-κB signaling events. Instead, we found that ELKS in addition to canonical IKKs interacts with the atypical IKK member IKKϵ. Furthermore, knockdown of K6a in hTCEpi cells promotes ELKS-dependent phosphoactivation of IKKϵ, which in turn phosphorylates and activates RelA. Our study thus demonstrated an unexpected role of cytosolic K6a as a novel negative regulator of TLR/NF-κB signaling in preventing excess proinflammatory cytokine and chemokine expressions. It further highlighted the functional importance of ELKS as a common signaling scaffold for both canonical and atypical IKK-dependent activation of NF-κB in corneal epithelial cells. Using both IKK classes other than only canonical IKKs for TLR/NF-κB induction as in other cell types including myeloid immune cells suggest that the cornea epithelium is more flexible in modulating its inflammatory response, which could greatly minimize corneal damage while preserving its essential functions for barrier protection and light refraction.

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Section: Introductionmentioning

confidence: 99%

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

Chan,

Sun,

Bhushan

et al. 2023

Preprint

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“…TRAFs play an important role in innate immunity by interacting with adapter proteins or other kinases to continue signaling cascades by polyubiquitination, which can then recruit other important kinases, such as TBK1, TAK1, and IKKs 77 . TRAF3 is one of the most functionally diverse of the TRAFs in particular in the regulation of non-canonical NFκB signaling pathways 81 . This is the first report of TRAF3 in E. scolopes and the sequences not only contained the usual TRAF domains but also had a seven in absentia (SIAH)-type zinc finger that is important in E3 ubiquitin ligases (Dataset S1 ).…”

Section: Resultsmentioning

confidence: 99%

Impact of modeled microgravity stress on innate immunity in a beneficial animal-microbe symbiosis

Duscher,

Vroom,

Foster

2024

Sci Rep

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The innate immune response is the first line of defense for all animals to not only detect invading microbes and toxins but also sense and interface with the environment. One such environment that can significantly affect innate immunity is spaceflight. In this study, we explored the impact of microgravity stress on key elements of the NFκB innate immune pathway. The symbiosis between the bobtail squid Euprymna scolopes and its beneficial symbiont Vibrio fischeri was used as a model system under a simulated microgravity environment. The expression of genes associated with the NFκB pathway was monitored over time as the symbiosis progressed. Results revealed that although the onset of the symbiosis was the major driver in the differential expression of NFκB signaling, the stress of simulated low-shear microgravity also caused a dysregulation of expression. Several genes were expressed at earlier time points suggesting that elements of the E. scolopes NFκB pathway are stress-inducible, whereas expression of other pathway components was delayed. The results provide new insights into the role of NFκB signaling in the squid-vibrio symbiosis, and how the stress of microgravity negatively impacts the host immune response. Together, these results provide a foundation to develop mitigation strategies to maintain host-microbe homeostasis during spaceflight.

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“…Next, we identified by NanoLuciferase two-hybrid assays and validated by co-affinity purification experiments the interaction between MGF505-4R and TRAF3. The latter plays a crucial role in the regulation of the IFN-α/β induction pathway mediated by Toll-like (TLR) receptors and RIG-I-like receptors (RLR) families ( 54 , 55 ). Upon activation of RIG-I, TRAF3 is recruited by MAVS, then promotes the ubiquitination of K63, providing a platform for NF-kappa-B essential modulator (NEMO) and TBK1/IKKϵ complex to activate IRF3 and initiates IFN-α/β expression ( 56 – 59 ).…”

Section: Discussionmentioning

confidence: 99%

Exploring type I interferon pathway: virulent vs. attenuated strain of African swine fever virus revealing a novel function carried by MGF505-4R

Dupré,

Le Dimna,

Hutet

et al. 2024

Front. Immunol.

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African swine fever virus represents a significant reemerging threat to livestock populations, as its incidence and geographic distribution have surged over the past decade in Europe, Asia, and Caribbean, resulting in substantial socio-economic burdens and adverse effects on animal health and welfare. In a previous report, we described the protective properties of our newly thermo-attenuated strain (ASFV-989) in pigs against an experimental infection of its parental Georgia 2007/1 virulent strain. In this new study, our objective was to characterize the molecular mechanisms underlying the attenuation of ASFV-989. We first compared the activation of type I interferon pathway in response to ASFV-989 and Georgia 2007/1 infections, employing both in vivo and in vitro models. Expression of IFN-α was significantly increased in porcine alveolar macrophages infected with ASFV-989 while pigs infected with Georgia 2007/1 showed higher IFN-α than those infected by ASFV-989. We also used a medium-throughput transcriptomic approach to study the expression of viral genes by both strains, and identified several patterns of gene expression. Subsequently, we investigated whether proteins encoded by the eight genes deleted in ASFV-989 contribute to the modulation of the type I interferon signaling pathway. Using different strategies, we showed that MGF505-4R interfered with the induction of IFN-α/β pathway, likely through interaction with TRAF3. Altogether, our data reveal key differences between ASFV-989 and Georgia 2007/1 in their ability to control IFN-α/β signaling and provide molecular mechanisms underlying the role of MGF505-4R as a virulence factor.

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The Roles of TRAF3 in Immune Responses

Cited by 19 publications

References 111 publications

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB

Impact of modeled microgravity stress on innate immunity in a beneficial animal-microbe symbiosis

Exploring type I interferon pathway: virulent vs. attenuated strain of African swine fever virus revealing a novel function carried by MGF505-4R

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