Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

Jin, Wei; Chang, Mikyoung; Sun, Shao Cong

doi:10.1038/cmi.2011.60

Cited by 52 publications

(54 citation statements)

References 100 publications

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“…We next used an LPS-induced septic-shock model to further investigate the in vivo function of TRIM29 in acute lung inflammation. In this acute model, death occurs within hours, mainly due to the production of TNF 30,31 . Age-matched wild-type and Trim29 −/− littermates were inoculated intranasally with LPS.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that both the RING domain and the B-box domain of TRIM18 have E3 ligase activity, although the B-box domain exhibits weaker E3 ligase activity than that of a typical RING domain 29 . Furthermore, the E3 ligase Peli1 does not contain a typical RING domain, which suggests that not all E3 ligases use a typical RING domain to catalyze ubiquitination 30,31 .…”

Section: Discussionmentioning

confidence: 99%

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Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract

Weng²,

et al. 2016

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The respiratory tract is heavily populated with innate immune cells, but the mechanisms that control such cells are poorly defined. Here we found that the E3 ubiquitin ligase TRIM29 was a selective regulator of the activation of alveolar macrophages, the expression of type I interferons and the production of proinflammatory cytokines in the lungs. We found that deletion of TRIM29 enhanced macrophage production of type I interferons and protected mice from infection with influenza virus, while challenge of Trim29−/− mice with Haemophilus influenzae resulted in lethal lung inflammation due to massive production of proinflammatory cytokines by macrophages. Mechanistically, we demonstrated that TRIM29 inhibited interferon-regulatory factors and signaling via the transcription factor NF-κB by degrading the adaptor NEMO and that TRIM29 directly bound NEMO and subsequently induced its ubiquitination and proteolytic degradation. These data identify TRIM29 as a key negative regulator of alveolar macrophages and might have important clinical implications for local immunity and immunopathology.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract

Weng²,

et al. 2016

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“…Importantly, the disease-coding variant is located in the RING domain, a domain with a predicted E3 ubiquitin-protein ligase activity. Ubiquitin ligases have been shown to regulate key adaptors of proinflammatory pathways [15]–[17]. We previously reported that RNF186 expression was higher in human intestinal tissues than in immune tissues [8].…”

Section: Discussionmentioning

confidence: 99%

Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

et al. 2013

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Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

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“…Mouse models have shown that IRAK2 is critical in sustaining late phase inflammatory responses after TLR stimulation, leading to increased production of inflammatory cytokines [21]. These molecules may also be important in T cell related functions, such as T cell tolerance [22], and promotion of Th17 cell development [23]. …”

Section: Discussionmentioning

confidence: 99%

Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD

Baines¹,

Hsu²,

Tooze³

et al. 2013

Respir Res

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BackgroundRhinovirus (RV) is a major cause of chronic obstructive pulmonary disease (COPD) exacerbations, and primarily infects bronchial epithelial cells. Immune responses from BECs to RV infection are critical in limiting viral replication, and remain unclear in COPD. The objective of this study is to investigate innate immune responses to RV infection in COPD primary BECs (pBECs) in comparison to healthy controls.MethodsPrimary bronchial epithelial cells (pBECs) from subjects with COPD and healthy controls were infected with RV-1B. Cells and cell supernatant were collected and analysed using gene expression microarray, qPCR, ELISA, flow cytometry and titration assay for viral replication.ResultsCOPD pBECs responded to RV-1B infection with an increased expression of antiviral and pro-inflammatory genes compared to healthy pBECs, including cytokines, chemokines, RNA helicases, and interferons (IFNs). Similar levels of viral replication were observed in both disease groups; however COPD pBECs were highly susceptible to apoptosis. COPD pBECs differed at baseline in the expression of 9 genes, including calgranulins S100A8/A9, and 22 genes after RV-1B infection including the signalling proteins pellino-1 and interleukin-1 receptor associated kinase 2. In COPD, IFN-β/λ1 pre-treatment did not change MDA-5/RIG-I and IFN-β expression, but resulted in higher levels IFN-λ1, CXCL-10 and CCL-5. This led to reduced viral replication, but did not increase pro-inflammatory cytokines.ConclusionsCOPD pBECs elicit an exaggerated pro-inflammatory and antiviral response to RV-1B infection, without changing viral replication. IFN pre-treatment reduced viral replication. This study identified novel genes and pathways involved in potentiating the inflammatory response to RV in COPD.

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Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

Cited by 52 publications

References 100 publications

Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract

Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract

Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD

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