The HECT-Type E3 Ubiquitin Ligase AIP2 Inhibits Activation-Induced T-Cell Death by Catalyzing EGR2 Ubiquitination

Chen, An; Gao, Beixue; Zhang, Jingping; McEwen, Tamara J.; Ye, Shui Q.; Zhang, Donna; Fang, Deyu

doi:10.1128/mcb.00407-09

Cited by 44 publications

(39 citation statements)

References 48 publications

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“…The ubiquitin ligase activity of WWP2 and the PXXY motif of Paip1 were critical for ubiquitination and degradation. Previous studies have demonstrated the involvement of WWP2 in the regulation of transcription, embryonic stem cell development, cellular transport, T-cell activation processes, and tumorigenesis by targeting distinct substrates (35). In the present study, we revealed that Paip1 is a novel substrate of WWP2.…”

Section: Discussionsupporting

confidence: 55%

Paip1, an Effective Stimulator of Translation Initiation, Is Targeted by WWP2 for Ubiquitination and Degradation

Zhang

Gao

2014

Molecular and Cellular Biology

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Section: Discussionsupporting

confidence: 55%

Paip1, an Effective Stimulator of Translation Initiation, Is Targeted by WWP2 for Ubiquitination and Degradation

Zhang

Gao

2014

Molecular and Cellular Biology

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“…Similar to previous studies, CD4 T cells were predominantly skewed to IFN-␥-producing Th1 cells (31%) with a small percentage of IL-4-producing Th2 cells (1.2%) when stimulated under nonpolarization conditions with anti-CD3 plus anti-CD28 (4,8). In contrast, c-Abl Ϫ/Ϫ T cells stimulated under the same condition produced more IL-4 ϩ cells (5.5%), while the percentage of IFN-␥ ϩ cells was decreased (17%) (Fig.…”

Section: Resultssupporting

confidence: 69%

c-Abl-Mediated Tyrosine Phosphorylation of the T-bet DNA-Binding Domain Regulates CD4⁺ T-Cell Differentiation and Allergic Lung Inflammation

Chen

Lee

Gao

et al. 2011

Molecular and Cellular Biology

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The tyrosine kinase c-Abl is required for full activation of T cells, while its role in T-cell differentiation has not been characterized. We report that c-Abl deficiency skews CD4 ؉ T cells to type 2 helper T cell (Th2) differentiation, and c-Abl ؊/؊ mice are more susceptible to allergic lung inflammation. c-Abl interacts with and phosphorylates T-bet, a Th1 lineage transcription factor. c-Abl-mediated phosphorylation enhances the transcriptional activation of T-bet. Interestingly, three tyrosine residues within the T-bet DNA-binding domain are the predominant sites of phosphorylation by c-Abl. Mutation of these tyrosine residues inhibits the promoter DNA-binding activity of T-bet. c-Abl regulates Th cell differentiation in a T-bet-dependent manner because genetic deletion of T-bet in CD4 ؉ T cells abolishes c-Abl-deficiency-mediated enhancement of Th2 differentiation. Reintroduction of T-bet-null CD4؉ T cells with wild-type T-bet, but not its tyrosine mutant, rescues gamma interferon (IFN-␥) production and inhibits Th2 cytokine production. Therefore, c-Abl catalyzes tyrosine phosphorylation of the DNA-binding domain of T-bet to regulate CD4 ؉ T cell differentiation.

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“…WWP2 is an E3 ubiquitin ligase containing a C-terminal HECT domain, four WW repeats, and an N-terminal C2 domain that may be important for its subcellular localization (17). It has been reported that WWP2 is involved in inhibition of activation-induced T-cell death by ubiquitinating EGR2 (18) as well as in early mammalian development by targeting the octamer-binding transcription factor 4 (Oct-4) (19). In addition, recent studies have suggested that WWP2 can facilitate the budding process of retrovirus (20).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, several studies have demonstrated that WWP2 is involved in regulating transcription, embryonic stem-cell fate, cellular transport, tumorigenesis, and T-cell activation processes by targeting distinct substrates (18)(19)(20). Recently, a gene knockout study revealed a developmental role for WWP2 in chondrogenesis via mechanisms involving cartilage-specific transcription factors (24).…”

Section: Discussionmentioning

confidence: 99%

E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation

Yang

Liao

Wang

et al. 2013

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

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Recognition of viral double-stranded RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-κB and interferon regulated factor 3, leading to induction of type I interferons and proinflammatory cytokines. TIR-domain-containing adapter-inducing interferon-β (TRIF) is an adapter protein required for TLR3-mediated signaling. Here we identified the E3 ubiquitin ligase WW domaincontaining protein 2 (WWP2) as a TRIF-associated protein by biochemical purification. WWP2 mediated K48-linked ubiquitination and degradation of TRIF upon TLR3 activation. Overexpression of WWP2 inhibited TLR3-mediated NF-κB and interferon regulated factor 3 activation, whereas knockdown of WWP2 had opposite effects. We generated Wwp2-deficient mice to further investigate the roles of Wwp2 in innate immune responses. Consistently, production of IFN-β, CCL5, TNFα, and IL-6 in response to the TLR3 ligand poly(I:C) was elevated in Wwp2 −/− macrophages and Wwp2-deficient mice exhibited increased susceptibility to poly(I:C)-induced death than the control littermates. Our findings suggest that WWP2 negatively regulates TLR3-mediated innate immune and inflammatory responses by targeting TRIF for ubiquitination and degradation.T oll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors (PRRs) that are critically involved in host defense from plants to humans. So far, 13 TLRs (named TLR1 to TLR13) have been identified in humans and mice, each of which recognizes a distinct set of pathogen-associated molecular patterns (PAMPs) (1). TLRs contain an extracellular domain consisting of leucine rich repeats which is responsible for PAMP recognition, a transmembrane domain, and a conserved cytoplasmic toll/IL-1 receptor (TIR) domain which is able to mediate homotypic protein-protein interactions (2). The TIR domains of TLRs are responsible for their homo-or hetero-dimerization, and upon ligand stimulation, they also act as platforms to recruit downstream TIR domain-containing adaptor proteins and signaling molecules, leading to the activation of transcription factors such as NF-κB and interferon regulated factor 3 (IRF3) (1, 3, 4). These transcription factors act alone or in collaboration to induce transcription of proinflammatory cytokines and/or type I interferons (IFNs).Among the TLRs, TLR3 has been reported to recognize viral dsRNA as well as its analog poly(I:C). Recognition of these ligands by TLR3 activates signaling pathways leading to the activation of NF-κB and IRF3 and subsequent production of type I IFNs and proinflammatory cytokines (5). TLR3-mediated signaling critically depends on the TIR domain-containing adapter TIRdomain-containing adapter-inducing interferon-β (TRIF; also called TICAM-1) (6). It has been shown that Trif −/− lung fibroblasts are defective in poly(I:C)-induced activation of NF-κB and IRF3 as well as production of type I IFNs, demonstrating that TRIF is indispensable for TLR3-mediated signaling (7). In addition, the TLR4 ligand LPS has been shown to signal through TRIF-...

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The HECT-Type E3 Ubiquitin Ligase AIP2 Inhibits Activation-Induced T-Cell Death by Catalyzing EGR2 Ubiquitination

Cited by 44 publications

References 48 publications

Paip1, an Effective Stimulator of Translation Initiation, Is Targeted by WWP2 for Ubiquitination and Degradation

Paip1, an Effective Stimulator of Translation Initiation, Is Targeted by WWP2 for Ubiquitination and Degradation

c-Abl-Mediated Tyrosine Phosphorylation of the T-bet DNA-Binding Domain Regulates CD4⁺ T-Cell Differentiation and Allergic Lung Inflammation

E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation

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The HECT-Type E3 Ubiquitin Ligase AIP2 Inhibits Activation-Induced T-Cell Death by Catalyzing EGR2 Ubiquitination

Cited by 44 publications

References 48 publications

Paip1, an Effective Stimulator of Translation Initiation, Is Targeted by WWP2 for Ubiquitination and Degradation

Paip1, an Effective Stimulator of Translation Initiation, Is Targeted by WWP2 for Ubiquitination and Degradation

c-Abl-Mediated Tyrosine Phosphorylation of the T-bet DNA-Binding Domain Regulates CD4+ T-Cell Differentiation and Allergic Lung Inflammation

E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation

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c-Abl-Mediated Tyrosine Phosphorylation of the T-bet DNA-Binding Domain Regulates CD4⁺ T-Cell Differentiation and Allergic Lung Inflammation