title: The CLRX.1/NOD24 (NLRP2P) pseudogene codes a functional negative regulator of NF-κB, pyrin-only protein 4.
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.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Porter
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Duffy
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Nyland
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Atianand
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sharifi
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Harton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011544:Pseudogenes / Q000235:genetics*; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D018626:Retroelements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D008070:Lipopolysaccharides; C495732:NLRP2 protein, human; C466775:NLRP4 protein, human; C498143:RELA protein, human; D012097:Repressor Proteins; D018626:Retroelements; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D012694:Serine