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Cutting Edge: K63-Linked Polyubiquitination of NEMO Modulates TLR Signaling and Inflammation In Vivo¹

Chang-Yuan Ni^*, Zhao-Hui Wu, William C. Florence^*, Vrajesh V. Parekh^*, Maria Pia Arrate^*, Steven Pierce^*, Brock Schweitzer^*, Luc Van Kaer^*, Sebastian Joyce^*, Shigeki Miyamoto, Dean W. Ballard^2,* and Eugene M. Oltz^2,*

^* Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232; and Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin, Madison, WI 53706

Transcription factor NF-B controls the expression of multiple genes involved in immunity and inflammation. The initial activation and duration of NF-B signaling is regulated by posttranslational modifications to IB kinase, which earmarks inhibitors of NF-B for degradation. Prior studies suggest that K63-linked ubiquitination of NEMO (NF-B essential modulator), an IB kinase regulatory subunit, is critical for NF-B and MAPK signaling following engagement of Ag receptors. We now demonstrate that NF-B and MAPK pathways are largely unaffected in primary cells from mice harboring a ubiquitination-defective form of NEMO, NEMO-KR. TLR- but not Ag receptor-induced cellular responses are impaired in NEMO-KR mice, which are more resistant to LPS-induced endotoxic shock than wild-type animals. Thus, one function of NEMO ubiquitination is to fine tune innate immune responses under TLR control.

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 is supported by National Institutes of Health Grants AI052379, CA082556, CA081065, AI070305, AI042284, AI061721, and HL068744 and by a grant from the Leukemia and Lymphoma Society (to Z.-H.W.).

² Address correspondence and reprint requests to Dr. Dean Ballard and Dr. Eugene Oltz, Department of Microbiology and Immunology, Vanderbilt University, 1161 21st Avenue South, Nashville, TN 37232. E-mail addresses: dean.ballard{at}vanderbilt.edu and eugene.oltz{at}vanderbilt.edu

³ Abbreviations used in this paper: AgR, Ag receptor; DC, dendritic cell; BMDC, bone marrow DC; ES, embryonic stem; IKK, IB kinase; KLH, keyhole limpet hemocyanin; NEMO, NF-B essential modulator; Neo, neomycin; PGK, phosphoglycerate kinase; TRAF6, TNFR-associated factor 6; Ub, ubiquitin; WT, wild type.

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The JI 2008 180: 7053-7054. [Full Text]  

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