Blau Syndrome–Associated Nod2 Mutation Alters Expression of Full-Length NOD2 and Limits Responses to Muramyl Dipeptide in Knock-in Mice
| Autor: | Eric Griffiths, Jae Dugan, Paige Snow, Brieanna Brown, Ellen Lee, Daniel W. Carr, Carlos D. Rose, Holly L. Rosenzweig, James T. Rosenbaum, Michael P. Davey |
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| Rok vydání: | 2015 |
| Předmět: |
Sarcoidosis
medicine.medical_treatment Immunology Nod2 Signaling Adaptor Protein Biology medicine.disease_cause p38 Mitogen-Activated Protein Kinases Article Cell Line Uveitis Mice chemistry.chemical_compound Receptor-Interacting Protein Serine-Threonine Kinase 2 Gene knockin NOD2 medicine Animals Humans Immunology and Allergy Gene Knock-In Techniques Phosphorylation RNA Small Interfering Blau syndrome Mutation Synovitis Interleukin-6 Arthritis Macrophages NF-kappa B Ubiquitination medicine.disease NFKB1 Molecular biology digestive system diseases Mice Inbred C57BL HEK293 Cells Cytokine chemistry Cancer research RNA Interference Mitogen-Activated Protein Kinases Signal transduction Acetylmuramyl-Alanyl-Isoglutamine Protein Processing Post-Translational Muramyl dipeptide Signal Transduction |
| Zdroj: | The Journal of Immunology. 194:349-357 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1402330 |
| Popis: | The biochemical mechanism by which mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) cause Blau syndrome is unknown. Several studies have examined the effect of mutations associated with Blau syndrome in vitro, but none has looked at the implication of the mutations in vivo. To test the hypothesis that mutated NOD2 causes alterations in signaling pathways downstream of NOD2, we created a Nod2 knock-in mouse carrying the most common mutation seen in Blau syndrome, R314Q (corresponding to R334Q in humans). The endogenous regulatory elements of mouse Nod2 were unaltered. R314Q mice showed reduced cytokine production in response to i.p. and intravitreal muramyl dipeptide (MDP). Macrophages from R314Q mice showed reduced NF-κB and IL-6 responses, blunted phosphorylation of MAPKs, and deficient ubiquitination of receptor-interacting protein 2 in response to MDP. R314Q mice expressed a truncated 80-kDa form of NOD2 that was most likely generated by a posttranslational event because there was no evidence for a stop codon or alternative splicing event. Human macrophages from two patients with Blau syndrome also showed a reduction of both cytokine production and phosphorylation of p38 in response to MDP, indicating that both R314Q mice and cells from patients with Blau syndrome show reduced responses to MDP. These data indicate that the R314Q mutation when studied with the Nod2 endogenous regulatory elements left intact is associated with marked structural and biochemical changes that are significantly different from those observed from studies of the mutation using overexpression, transient transfection systems. |
| Databáze: | OpenAIRE |
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