TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
PLoS ONE (Impact Factor: 3.23). 07/2012; 7(7):e41255. DOI: 10.1371/journal.pone.0041255
Source: PubMed


NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohn's disease. We found that TRIM27 expression is increased in Crohn's disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus.
We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases.

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Available from: Thomas Kufer, Oct 07, 2015
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    • "We interpret this dichotomy as a part of the well-tuned circuitry in response to microbial challenge: whereas autophagy is activated as an antimicrobial effector mechanism, the stimulatory inputs into the system mediated by NOD2 are downregulated lest the system overcommits, which in turn may result in detrimental consequences for the host. PAMP (e.g., MDP) tolerance is an important mechanism to avoid septic shock, which is in part achieved by NOD2 degradation (Zurek et al., 2012). "
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    ABSTRACT: IRGM, encoded by a uniquely human gene conferring risk for inflammatory diseases, affects autophagy through an unknown mechanism. Here, we show how IRGM controls autophagy. IRGM interacts with ULK1 and Beclin 1 and promotes their co-assembly thus governing the formation of autophagy initiation complexes. We further show that IRGM interacts with pattern recognition receptors including NOD2. IRGM, NOD2, and ATG16L1, all of which are Crohn's disease risk factors, form a molecular complex to modulate autophagic responses to microbial products. NOD2 enhances K63-linked polyubiquitination of IRGM, which is required for interactions of IRGM with the core autophagy factors and for microbial clearance. Thus, IRGM plays a direct role in organizing the core autophagy machinery to endow it with antimicrobial and anti-inflammatory functions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Cell 01/2016; In press Corrected proofs online. DOI:10.1016/j.molcel.2015.03.020 · 14.02 Impact Factor
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    • "One subset of Trim proteins that include Trim5, Trim14, Trim15, and Trim44 has been shown to positively regulate the antiviral response by ubiquitinating multiple targets in the pathway (Ottosson et al., 2006; Reymond et al., 2001; Uchil et al., 2013; Yang et al., 2013). On the other hand, Trim21, Trim27, Trim30 and Trim38 were recently shown to function as negative regulators of the antiviral response by mediating proteasomal degradation of various signaling factors (Higgs et al., 2008; Shi et al., 2008; Zhao et al., 2012; Zurek et al., 2012). Interestingly, some Trims like Trim21 are functionally flexible and can regulate the innate immune pathway in a positive or negative manner. "
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    ABSTRACT: In this study, using an immunoprecipitation coupled with mass spectrometry approach, we have identified the E3 ubiquitin ligase Trim21 as an interacting partner of IFI35 and Nmi. We found that this interaction leads to K63-linked ubiquitination on K22 residue of Nmi, but not IFI35. Using domain deletion analysis, we found that the interaction is mediated via the coiled-coil domain of Nmi and the carboxyl-terminal SPRY domain of Trim21. Furthermore, we show that depletion of Trim21 leads to significantly reduced interaction of Nmi with IFI35, which results in the abrogation of the negative regulatory function of the Nmi-IFI35 complex on innate antiviral signaling. Thus, Trim21 appears to be a critical regulator of the functions of the Nmi-IFI35 complex. Overall, the results presented here uncover a new mechanism of regulation of the Nmi-IFI35 complex by Trim21, which may have implications for various autoimmune diseases associated uncontrolled antiviral signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 09/2015; 485:383-392. DOI:10.1016/j.virol.2015.08.013 · 3.32 Impact Factor
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    • "Other roles for Ub in the regulation of NOD1 and NOD2 signaling have been revealed. For example, NOD2 is destabilized by Lys48-linked pUb and subsequent degradation via the E3 ligase TRIM27 (Lee et al., 2012; Zurek et al., 2012). This might partially account for the phenomenon of MDP tolerance, where MDP pretreatment significantly decreases subsequent NOD2 activation upon restimulation with MDP in both human cells (Hedl et al., 2007) and mouse cells (Kim et al., 2008a). "
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    ABSTRACT: The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders. Copyright © 2014 Elsevier Inc. All rights reserved.
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