A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling.
Nod2 is an intracellular sensor of a specific bacterial cell wall component, muramyl dipeptide, and activation of Nod2 stimulates an inflammatory response. Specific mutations of Nod2 have been associated with two inflammatory diseases, Crohn disease and Blau syndrome, and are thought to contribute to disease susceptibility through altering Nod2 signaling. Association of disease with inappropriate activation of Nod2 highlights the importance of proper regulation of Nod2 activity. However, little is known about specific regulation of the Nod2 pathway. We performed a biochemical screen to discover potential regulators of Nod2 and identified Erbin, a protein involved in cell polarity, receptor localization, and regulation of the mitogen-activated protein kinase pathway, as a novel Nod2-interacting protein. In our studies, we demonstrate specific interaction of Erbin and Nod2 both in vitro and in vivo and characterize the regions required for interaction in both proteins. We found that Nod2-dependent activation of NF-kappaB and cytokine secretion is inhibited by Erbin overexpression, whereas Erbin-/- mouse embryo fibroblasts show an increased sensitivity to muramyl dipeptide. These studies identify Erbin as a regulator of Nod2 signaling and demonstrate a novel role for Erbin in inflammatory responses.
McDonald
Christine
C
Department of Pathology, University of Michigan Medical School & Comprehensive Cancer Center, Ann Arbor, Michigan, 48109, USA.
Chen
Felicia F
FF
Ollendorff
Vincent
V
Ogura
Yasunori
Y
Marchetto
Sylvie
S
Lécine
Patrick
P
Borg
Jean-Paul
JP
Nuñez
Gabriel
G
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D013997:Time Factors; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D016207:Cytokines; C413364:ERBIN protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D008156:Luciferases