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Molecular and Cellular Biology, March 2008, p. 1841-1850, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01468-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

ATP Binding by Monarch-1/NLRP12 Is Critical for Its Inhibitory Function{triangledown} ,{ddagger}

Zhengmao Ye,1,{dagger} John D. Lich,2,{dagger} Chris B. Moore,2 Joseph A. Duncan,3 Kristi L. Williams,2,4 and Jenny P.-Y. Ting1,2*

Department of Microbiology and Immunology,1 Lineberger Comprehensive Cancer Center,2 Department of Medicine, Division of Infectious Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295,3 Departments of Cell Biology and Immunology, Duke University, Durham, North Carolina 277104

Received 14 August 2007/ Returned for modification 27 September 2007/ Accepted 14 December 2007

The recently discovered nucleotide binding domain-leucine rich repeat (NLR) gene family is conserved from plants to mammals, and several members are associated with human autoinflammatory or immunodeficiency disorders. This family is defined by a central nucleotide binding domain that contains the highly conserved Walker A and Walker B motifs. Although the nucleotide binding domain is a defining feature of this family, it has not been extensively studied in its purified form. In this report, we show that purified Monarch-1/NLRP12, an NLR protein that negatively regulates NF-{kappa}B signaling, specifically binds ATP and exhibits ATP hydrolysis activity. Intact Walker A/B motifs are required for this activity. These motifs are also required for Monarch-1 to undergo self-oligomerization, Toll-like receptor- or CD40L-activated association with NF-{kappa}B-inducing kinase (NIK) and interleukin-1 receptor-associated kinase 1 (IRAK-1), degradation of NIK, and inhibition of IRAK-1 phosphorylation. The stable expression of a Walker A/B mutant in THP-1 monocytes results in increased production of proinflammatory cytokines and chemokines to an extent comparable to that in cells in which Monarch-1 is silenced via short hairpin RNA. The results of this study are consistent with a model wherein ATP binding regulates the anti-inflammatory activity of Monarch-1.

* Corresponding author. Mailing address: University of North Carolina, CB7295, 450 West St., Chapel Hill, NC 27599. Phone: (919) 966-5538. Fax: (919) 966-8212. E-mail: jenny_ting{at}med.unc.edu

{triangledown} Published ahead of print on 26 December 2007.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, March 2008, p. 1841-1850, Vol. 28, No. 5
0270-7306/08/$08.00+0     doi:10.1128/MCB.01468-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lord, C. A., Savitsky, D., Sitcheran, R., Calame, K., Wright, J. R., Ting, J. P.-Y., Williams, K. L. (2009). Blimp-1/PRDM1 Mediates Transcriptional Suppression of the NLR Gene NLRP12/Monarch-1. J. Immunol. 182: 2948-2958 [Abstract] [Full Text]  


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