Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

Shuo Yang; Bingwei Wang; Fiachra Humphries; Ruaidhri Jackson; Marc E Healy; Ronan Bergin; Gabriella Aviello; Barry Hall; Deirdre McNamara; Trevor Darby; Aoife Quinlan; Fergus Shanahan; Silvia Melgar; Padraic G Fallon; Paul N Moynagh

doi:10.1038/ni.2669

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

Shuo Yang, Bingwei Wang, Fiachra Humphries, Ruaidhri Jackson, Marc E Healy, Ronan Bergin, Gabriella Aviello, Barry Hall, Deirdre McNamara, Trevor Darby, Aoife Quinlan, Fergus Shanahan, Silvia Melgar, Padraic G Fallon, Paul N Moynagh

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

68 Citations (Scopus)

Abstract

Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohn's disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction of cytokines after engagement of Nod2 and had exacerbated disease in various experimental models of colitis. Furthermore, expression of Pellino3 was lower in the colons of patients with Crohn's disease. Pellino3 directly bound to the kinase RIP2 and catalyzed its ubiquitination. Loss of Pellino3 led to attenuation of Nod2-induced ubiquitination of RIP2 and less activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs). Our findings identify RIP2 as a substrate for Pellino3 and Pellino3 as an important mediator in the Nod2 pathway and regulator of intestinal inflammation.

Original language	English
Pages (from-to)	927-936
Number of pages	10
Journal	Nature Immunology
Volume	14
Issue number	9
DOIs	https://doi.org/10.1038/ni.2669
Publication status	Published - Sep 2013

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Animals
Citrobacter rodentium
Colitis
Crohn Disease
Disease Models, Animal
Female
Gene Expression
Humans
Male
Mice
Mice, Knockout
Middle Aged
Nod2 Signaling Adaptor Protein
Protein Binding
Protein Interaction Domains and Motifs
Receptor-Interacting Protein Serine-Threonine Kinases
Signal Transduction
Ubiquitin-Protein Ligases
Ubiquitination
Young Adult
Journal Article
Research Support, Non-U.S. Gov't

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@article{fe477e4d5a2946469a6f7ebcf6a7f547,

title = "Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis",

abstract = "Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohn's disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction of cytokines after engagement of Nod2 and had exacerbated disease in various experimental models of colitis. Furthermore, expression of Pellino3 was lower in the colons of patients with Crohn's disease. Pellino3 directly bound to the kinase RIP2 and catalyzed its ubiquitination. Loss of Pellino3 led to attenuation of Nod2-induced ubiquitination of RIP2 and less activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs). Our findings identify RIP2 as a substrate for Pellino3 and Pellino3 as an important mediator in the Nod2 pathway and regulator of intestinal inflammation.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Animals, Citrobacter rodentium, Colitis, Crohn Disease, Disease Models, Animal, Female, Gene Expression, Humans, Male, Mice, Mice, Knockout, Middle Aged, Nod2 Signaling Adaptor Protein, Protein Binding, Protein Interaction Domains and Motifs, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination, Young Adult, Journal Article, Research Support, Non-U.S. Gov't",

author = "Shuo Yang and Bingwei Wang and Fiachra Humphries and Ruaidhri Jackson and Healy, {Marc E} and Ronan Bergin and Gabriella Aviello and Barry Hall and Deirdre McNamara and Trevor Darby and Aoife Quinlan and Fergus Shanahan and Silvia Melgar and Fallon, {Padraic G} and Moynagh, {Paul N}",

note = "We thank P.A. Barker and M. Saleh (McGill University) for Flag-tagged RIP2 and Nod2; M. Parkers and the Broad Institute for help and use of the Ricopili search tool; and G. Holleran for assistance in collecting biopsy samples from human subjects. Supported by Science Foundation Ireland (07/IN.1/B972 to P.N.M.; 10/IN.1/B3004 to P.G.F.; 02/CE/B124 and 07/CE/B1368 to F.S.; and funding for the Alimentary Pharmabiotic Centre as a Centre for Science, Engineering and Technology) and the Health Research Board of Ireland (PhD/2007/09).",

year = "2013",

month = sep,

doi = "10.1038/ni.2669",

language = "English",

volume = "14",

pages = "927--936",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

AU - Yang, Shuo

AU - Wang, Bingwei

AU - Humphries, Fiachra

AU - Jackson, Ruaidhri

AU - Healy, Marc E

AU - Bergin, Ronan

AU - Aviello, Gabriella

AU - Hall, Barry

AU - McNamara, Deirdre

AU - Darby, Trevor

AU - Quinlan, Aoife

AU - Shanahan, Fergus

AU - Melgar, Silvia

AU - Fallon, Padraic G

AU - Moynagh, Paul N

N1 - We thank P.A. Barker and M. Saleh (McGill University) for Flag-tagged RIP2 and Nod2; M. Parkers and the Broad Institute for help and use of the Ricopili search tool; and G. Holleran for assistance in collecting biopsy samples from human subjects. Supported by Science Foundation Ireland (07/IN.1/B972 to P.N.M.; 10/IN.1/B3004 to P.G.F.; 02/CE/B124 and 07/CE/B1368 to F.S.; and funding for the Alimentary Pharmabiotic Centre as a Centre for Science, Engineering and Technology) and the Health Research Board of Ireland (PhD/2007/09).

PY - 2013/9

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N2 - Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohn's disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction of cytokines after engagement of Nod2 and had exacerbated disease in various experimental models of colitis. Furthermore, expression of Pellino3 was lower in the colons of patients with Crohn's disease. Pellino3 directly bound to the kinase RIP2 and catalyzed its ubiquitination. Loss of Pellino3 led to attenuation of Nod2-induced ubiquitination of RIP2 and less activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs). Our findings identify RIP2 as a substrate for Pellino3 and Pellino3 as an important mediator in the Nod2 pathway and regulator of intestinal inflammation.

AB - Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohn's disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction of cytokines after engagement of Nod2 and had exacerbated disease in various experimental models of colitis. Furthermore, expression of Pellino3 was lower in the colons of patients with Crohn's disease. Pellino3 directly bound to the kinase RIP2 and catalyzed its ubiquitination. Loss of Pellino3 led to attenuation of Nod2-induced ubiquitination of RIP2 and less activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs). Our findings identify RIP2 as a substrate for Pellino3 and Pellino3 as an important mediator in the Nod2 pathway and regulator of intestinal inflammation.

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KW - Adult

KW - Aged

KW - Aged, 80 and over

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KW - Colitis

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KW - Disease Models, Animal

KW - Female

KW - Gene Expression

KW - Humans

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Middle Aged

KW - Nod2 Signaling Adaptor Protein

KW - Protein Binding

KW - Protein Interaction Domains and Motifs

KW - Receptor-Interacting Protein Serine-Threonine Kinases

KW - Signal Transduction

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ni.2669

DO - 10.1038/ni.2669

M3 - Article

C2 - 23892723

VL - 14

SP - 927

EP - 936

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 9

ER -

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

Abstract

Keywords

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