TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

Zurek, Birte; Schoultz, Ida; Neerincx, Andreas; Napolitano, L.M.; Birkner, Katharina; Bennek, Eveline; Sellge, Gernot; Lerm, Maria; Meroni, Germana; Söderholm, Johan D.; Kufer, Thomas A.

doi:10.1371/journal.pone.0041255

Cited by 97 publications

(74 citation statements)

References 88 publications

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“…In contrast, TRIM21 negatively regulates type I IFN production mainly through promoting K48-linked ubiquitination and degradation of DDX41 [35]. Recently, TRIM27 was described to act as an E3 ligase that negatively regulates NOD2 by mediating its ubiquitination and proteasomal degradation [36]. Here we show that TRIM27 is a key E3 ligase that mediates K48-linked ubiquitination at Lys251 and Lys372 of TBK1 and promotes TBK1 proteasomal degradation, thus functioning as a negative regulator of type I IFN production.…”

Section: Discussionmentioning

confidence: 57%

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

et al. 2015

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Type I interferon (IFN) production plays pivotal roles in host antiviral innate immune responses, but an excessive production of type I IFN leads to the development of immunopathological conditions. Investigations on the regulatory mechanisms underlying host type I IFN production are currently of great interest. Here, we found that the expression of lectin family member Siglec1 was upregulated by viral infection in macrophages, which was dependent on the IFN/JAK/STAT1 signaling pathway. Siglec1 was found to negatively regulate viral infection-triggered type I IFN production. Mechanistically, Siglec1 associates with DAP12 to recruit and activate the scaffolding function of SHP2; SHP2 then recruits E3 ubiquitin ligase TRIM27, which induces TBK1 degradation via K48-linked ubiquitination at Lys251 and Lys372. Therefore, viral infection-induced upregulation of Siglec1 feedback loop inhibits type I IFN production and suppresses antiviral innate immune responses. Our study outlines a novel mechanism of negative regulation of type I IFN production, which may help virus to escape immune elimination.

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Section: Discussionmentioning

confidence: 57%

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

et al. 2015

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“…TRIM27 functions as an E3 ubiquitin ligase (20) and is capable of conjugating various types of polyubiquitin chains to different substrates. Ubiquitination by TRIM27 modulates the activity of a given substrate rather than inducing its proteasomal degradation with the exception of NOD2 which it degrades (21). Ubiquitination by TRIM27 reduces the activity of PIK3C2B in T cells (22), inhibits PTEN to activate AKT1 (23), modifies WASH1 of the WASH regulatory complex to facilitate actin polymerization (24), and upregulates USP7-dependent deubiquitination of RIPK1 in tumor necrosis factor (TNF)-dependent apoptosis (25).…”

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confidence: 99%

Identification of TRIM27 as a Novel Degradation Target of Herpes Simplex Virus 1 ICP0

Conwell

White

Harper

et al. 2015

J Virol

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The herpes simplex virus 1 (HSV-1) immediate early protein ICP0 performs many functions during infection, including transactivation of viral gene expression, suppression of innate immune responses, and modification and eviction of histones from viral chromatin. Although these functions of ICP0 have been characterized, the detailed mechanisms underlying ICP0's complex role during infection warrant further investigation. We thus undertook an unbiased proteomic approach to identifying viral and cellular proteins that interact with ICP0 in the infected cell. Cellular candidates resulting from our analysis included the ubiquitinspecific protease USP7, the transcriptional repressor TRIM27, DNA repair proteins NBN and MRE11A, regulators of apoptosis, including BIRC6, and the proteasome. We also identified two HSV-1 early proteins involved in nucleotide metabolism, U L 39 and U L 50, as novel candidate interactors of ICP0. Because TRIM27 was the most statistically significant cellular candidate, we investigated the relationship between TRIM27 and ICP0. We observed rapid, ICP0-dependent loss of TRIM27 during HSV-1 infection. TRIM27 protein levels were restored by disrupting the RING domain of ICP0 or by inhibiting the proteasome, arguing that TRIM27 is a novel degradation target of ICP0. A mutant ICP0 lacking E3 ligase activity interacted with endogenous TRIM27 during infection as demonstrated by reciprocal coimmunoprecipitation and supported by immunofluorescence data. Surprisingly, ICP0-null mutant virus yields decreased upon TRIM27 depletion, arguing that TRIM27 has a positive effect on infection despite being targeted for degradation. These results illustrate a complex interaction between TRIM27 and viral infection with potential positive or negative effects of TRIM27 on HSV under different infection conditions. IMPORTANCEDuring productive infection, a virus must simultaneously redirect multiple cellular pathways to replicate itself while evading detection by the host's defenses. To orchestrate such complex regulation, viruses, including herpes simplex virus 1 (HSV-1), rely on multifunctional proteins such as the E3 ubiquitin ligase ICP0. This protein regulates various cellular pathways concurrently by targeting a diverse set of cellular factors for degradation. While some of these targets have been previously identified and characterized, we undertook a proteomic screen to identify additional targets of this activity to further characterize ICP0's role during infection. We describe a set of candidate interacting proteins of ICP0 identified through this approach and our characterization of the most statistically significant result, the cellular transcriptional repressor TRIM27. We present TRIM27 as a novel degradation target of ICP0 and describe the relationship of these two proteins during infection. During lytic infection, a virus must hijack the synthesis machinery of its host cell to manufacture its own components. The virus redirects cellular metabolism, chromatin regulation, transcription factors, and t...

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“…Shiina et al (2007) found the TRIM27 gene in a region of the chicken MHC-B using an extended gene map. Zurek et al (2012) reported that TRIM27 could degrade NOD2 to negatively regulate NOD2-mediated signalling, suggesting that TRIM27 could be a new candidate target of drug intervention in NOD2-associated diseases. Zoumpoulidou et al (2012) reported that the expression of TRIM27 was a modifier of disease incidence and progression and was related to the development of common human cancers, suggesting that TRIM27 is a potential target for intervention in cancer.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of antibody level response to NDV and IBV in Jinghai yellow chicken based on SLAF-seq technology

WenHao

Zhang

et al. 2015

J Appl Genetics

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Newcastle disease (ND) and avian infectious bronchitis (IB) are contagious diseases of chickens. To identify genes associated with antibody levels against ND and IB, a genome-wide association study was performed using specific-locus amplified fragment sequencing (SLAF-seq) technology in Jinghai yellow chickens. This determined six single-nucleotide polymorphisms (SNPs) that were associated with antibody levels against Newcastle disease virus (NDV): rsZ2494661, rsZ2494710, rs1211307701, rs1211307711, rs1218289310 and rs420701988. Of these, rsZ2494661 and rsZ2494710 reached the 5 % Bonferroni genome-wide significance level (5.5E-07) and they were both 134.7 kb downstream of the SETBP1 gene. The remaining four SNPs had 'suggestive' genome-wide significance levels (1.1E-05) and they were within or near the Plexin B1, LRRN1 and PDGFC genes. IB had two SNPs associated with antibody levels: rs149988433 and rs16170823; both reached chromosome-wide significance levels and they were near the USP7 and TRIM27 genes, respectively. Bioinformatics, GO annotation and pathway analysis indicated that five of these genes (Plexin B1, TRIM27, PDGFC, SETBP1 and USP7) may be important for the generation of protective antibodies against NDV and infectious bronchitis virus (IBV). This paves the way for further research on host immune responses against NDV.

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TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

Cited by 97 publications

References 88 publications

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

Identification of TRIM27 as a Novel Degradation Target of Herpes Simplex Virus 1 ICP0

Genome-wide association study of antibody level response to NDV and IBV in Jinghai yellow chicken based on SLAF-seq technology

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