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The CLRX.1/NOD24 (NLRP2P) pseudogene codes a functional negative regulator of NF-κB, pyrin-only protein 4

Genes & Immunity volume 15, pages 392–403 (2014)Cite this article

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Abstract

Pseudogenes are duplicated yet defunct copies of functional parent genes. However, some pseudogenes have gained or retained function. In this study, we consider a functional role for the NLRP2-related, higher primate-specific, processed pseudogene NLRP2P, which is closely related to Pyrin-only protein 2 (POP2/PYDC2), a regulator of nuclear factor-κB (NF-κB) and the inflammasome. The NLRP2P open-reading frame on chromosome X has features consistent with a processed pseudogene (retrotransposon), yet encodes a 45-amino-acid, Pyrin-domain-related protein. The open-reading frame of NLRP2P shares 80% identity with POP2 and is under purifying selection across Old World primates. Although widely expressed, NLRP2P messenger RNA is upregulated by lipopolysaccharide in human monocytic cells. Functionally, NLRP2P impairs NF-κB p65 transactivation by reducing activating phosphorylation of RelA/p65. Reminiscent of POP2, NLRP2P reduces production of the NF-κB-dependent cytokines tumor necrosis factor alpha and interleukin (IL)-6 following toll-like receptor stimulation. In contrast to POP2, NLRP2P fails to inhibit the ASC-dependent NLRP3 inflammasome. In addition, beyond regulating cytokine production, NLRP2P has a potential role in cell cycle regulation and cell death. Collectively, our findings suggest that NLRP2P is a resurrected processed pseudogene that regulates NF-κB RelA/p65 activity and thus represents the newest member of the POP family, POP4.

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Acknowledgements

We thank Dr James R Drake for critical review of this manuscript, Dr Carlos M de Noronha for reagents, Amithi Narendran for technical support and the AMC Immunology Core. This work was supported by National Research Service Award (1F32AI100473-01) to KAP and National Institutes of Health grant (R01AI072259) awarded to JAH.

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  1. M K Atianand

    Present address: 2Current address: Division of Infectious Diseases, University of Massachusetts Medical School, LRB, Rm 370M, 364 Plantation Street, Worcester, MA 01605, USA.,

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  1. Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA

    K A Porter, E B Duffy, P Nyland, M K Atianand, H Sharifi & J A Harton

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  1. K A Porter
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Porter, K., Duffy, E., Nyland, P. et al. The CLRX.1/NOD24 (NLRP2P) pseudogene codes a functional negative regulator of NF-κB, pyrin-only protein 4. Genes Immun 15, 392–403 (2014). https://doi.org/10.1038/gene.2014.30

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