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 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 mRNA is upregulated by LPS 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 TNFα and IL-6 following TLR 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.

Toward a Reference Gene Catalog of Human Primary Monocytes

“…The expression of 2819 pseudogenes was detected in our datasets (Supplementary Table S5). Although pseudogenes were known as genomic fossils for several years, some studies have reported that pseudogenes could play critical roles in regulation of their parent genes, and many pseudogenes were transcribed into RNA (Porter et al, 2014;Tian et al, 2007). We identified the high expression of two functional pseudogenes, including MORF4 (mortality factor 4) (Yochum and Ayer, 2002) and MEIS3P1 (Meis homeobox 3 pseudogene 1) (Tian et al, 2007), in our datasets, which have been reported to act as TFs.…”

“…Pseudogenes are copies of protein-coding genes that arise from genomic duplication or retrotransposition of mRNA sequences into the genome, followed by accumulation of deleterious mutations due to loss of selection pressure, degenerating eventually into so-called genetic fossils (Porter et al, 2014). The expression of 2819 pseudogenes was detected in our datasets (Supplementary Table S5).…”

Network analysis of pseudogene-gene relationships: from pseudogene evolution to their functional potentials

“…An example is CCR5 which has a known pseudogene polymorphism in human that is known for reduced risk of HIV infection in exposed individuals 32,33 . PGG family 1149 is of interest because it contains the proto-oncogene RELA which has been implicated in pseudogene regulatory activity 34,35 . Another family of interest is 1235 that contains SOX2, which has been identified as a member of ceRNA networks 36,37 .…”

An updated view on the structure and function of PYRIN domains

“…Recently, a fourth POP, POP4, has been predicted, which is encoded by the pseudogene NLRP2P and shares 80% identity with POP2 [104]. Although the α1 helix of POP4 is highly similar to the one in POP2, it lacks the acidic residues at positions 6 and 16 that are present in POP2, which prevents POP4 from binding to ASC and inhibiting inflammasomes [104].…”

“…Although the α1 helix of POP4 is highly similar to the one in POP2, it lacks the acidic residues at positions 6 and 16 that are present in POP2, which prevents POP4 from binding to ASC and inhibiting inflammasomes [104]. However, it retained its inhibitory effect on NF-κB activation.…”