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TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

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...

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Autores principales: Zurek, Birte, Schoultz, Ida, Neerincx, Andreas, Napolitano, Luisa M., Birkner, Katharina, Bennek, Eveline, Sellge, Gernot, Lerm, Maria, Meroni, Germana, Söderholm, Johan D., Kufer, Thomas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400628/
https://www.ncbi.nlm.nih.gov/pubmed/22829933
http://dx.doi.org/10.1371/journal.pone.0041255
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author Zurek, Birte
Schoultz, Ida
Neerincx, Andreas
Napolitano, Luisa M.
Birkner, Katharina
Bennek, Eveline
Sellge, Gernot
Lerm, Maria
Meroni, Germana
Söderholm, Johan D.
Kufer, Thomas A.
author_facet Zurek, Birte
Schoultz, Ida
Neerincx, Andreas
Napolitano, Luisa M.
Birkner, Katharina
Bennek, Eveline
Sellge, Gernot
Lerm, Maria
Meroni, Germana
Söderholm, Johan D.
Kufer, Thomas A.
author_sort Zurek, Birte
collection PubMed
description 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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spelling pubmed-34006282012-07-24 TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation Zurek, Birte Schoultz, Ida Neerincx, Andreas Napolitano, Luisa M. Birkner, Katharina Bennek, Eveline Sellge, Gernot Lerm, Maria Meroni, Germana Söderholm, Johan D. Kufer, Thomas A. PLoS One Research Article 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. Public Library of Science 2012-07-19 /pmc/articles/PMC3400628/ /pubmed/22829933 http://dx.doi.org/10.1371/journal.pone.0041255 Text en Zurek et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zurek, Birte
Schoultz, Ida
Neerincx, Andreas
Napolitano, Luisa M.
Birkner, Katharina
Bennek, Eveline
Sellge, Gernot
Lerm, Maria
Meroni, Germana
Söderholm, Johan D.
Kufer, Thomas A.
TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation
title TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation
title_full TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation
title_fullStr TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation
title_full_unstemmed TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation
title_short TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation
title_sort trim27 negatively regulates nod2 by ubiquitination and proteasomal degradation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400628/
https://www.ncbi.nlm.nih.gov/pubmed/22829933
http://dx.doi.org/10.1371/journal.pone.0041255
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