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Cutting Edge: Monarch-1 Suppresses Non-Canonical NF-B Activation and p52-Dependent Chemokine Expression in Monocytes¹

Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, NC 27599

CATERPILLER (NOD, NBD-LRR) proteins are rapidly emerging as important mediators of innate and adaptive immunity. Among these, Monarch-1 operates as a novel attenuating factor of inflammation by suppressing inflammatory responses in activated monocytes. However, the molecular mechanisms by which Monarch-1 performs this important function are not well understood. In this report, we show that Monarch-1 inhibits CD40-mediated activation of NF-B via the non-canonical pathway in human monocytes. This inhibition stems from the ability of Monarch-1 to associate with and induce proteasome-mediated degradation of NF-B inducing kinase. Congruently, silencing Monarch-1 with shRNA enhances the expression of p52-dependent chemokines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI063031, DEO16326, DK38108, and SERCEB A1-02-031 (to J.P-Y.T.). J.D.L. is supported by The American Cancer Society. J.C.A. is supported by National Institutes of Health Training Grant T32-A1007273–22. K.L.W. is supported by National Institutes of Health Institutional Postdoctoral Fellowship and in part by the Amgen/Federation of Clinical Immunology Societies Fellowship Award. B.K.D. is supported by the Crohn’s and Colitis Foundation of America. C.B.M. is supported by the Juvenile Diabetes Research Foundation. J.P-Y.T. is a recipient of a Senior Investigator Award of the Sandler Program in Asthma Research.

² Address correspondence and reprint requests to Dr. Jenny P-Y. Ting, Lineberger Comprehensive Cancer Center, University of North Carolina, 102 Mason Farm Road, CB7295, Chapel Hill, NC 27599. E-mail address: jenny_ting{at}med.unc.edu

³ Abbreviations used in this paper: NIK, NF-B-inducing kinase; Ha, hemagglutinin; IKK, IB kinase; NOD, nucleotide-binding oligomerization domain; NBD, nucleotide binding domain; LRR, leucine-rich repeat.

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