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.
Pyrin-only proteins influence NF-kB and inflammasome signaling pathways. In viruses, POPs act as pathogenic factors by reducing innate immune responses and favoring viral survival within the host. In humans, two known POPs are thought to have a role in regulating innate immunity and inflammation. POP1 interferes with IKKα/β activation and prevents the downstream activation of NF-kB with no known effect on ASC-dependent inflammasomes. POP2 however, inhibits NF-kB signaling at the level of the p65 (RelA) subunit and down-modulates the formation and activation of a variety of pyrin domain/ASC-dependent inflammasomes. Here we describe a third human POP, POP3, the product of an NLRP pseudogene encoded on chromosome X that is expressed in a wide variety of tissues. Like its close genetic relative POP2, POP3 inhibits p65 activation downstream of IKK, but lacks the capacity of inhibit the NLRP3 inflammasome. Our data suggest that the human POP family has three members, all of which may play distinct biological roles during inflammation.
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