This invention provides a novel pyrin-only
protein (POP2), polypeptides, nucleic acids encoding them and methods for making and using them. The polypeptides of this invention have nuclear factor-κB (NF-κB) modulating activity. NF-κB is pivotal for
transactivation of
cell-cycle regulatory,
cytokine and adhesion molecule genes and is dysregulated in many cancers, neurodegenerative disorders, and inflammatory diseases. Proteins with Pyrin and / or
caspase recruitment (CARD) domains have roles in
apoptosis, innate
immunity, and
inflammation. Many pyrin domain proteins modulate NF-KB activity as well as participate in assembling both the perinuclear “apoptotic speck” and the pro-IL1β / IL-18 converting
inflammasome complex. ‘Pyrin-only’ proteins are attractive as negative regulators of pyrin domain-mediated functions and one such
protein, POP1, has been reported. We teach a second Pyrin-only
protein (POP2). POP2 is a 294 nt single
exon gene located on human
chromosome 3 encoding a 97
amino acid protein with sequence and predicted
structural similarity to other pyrin domains. Highly similar to pyrin domains in CATERPILLER (CLR, NLR, NALP) family proteins, POP2 is less like the prototypic Pyrin and ASC pyrin domains. POP2 is expressed principally in
peripheral blood leukocytes and displays both cytoplasmic and nuclear expression patterns in transfected cells. TNFα-stimulated and p65 (
RelA) induced NF-KB-dependent
gene transcription is inhibited by POP2
in vitro by a mechanism involving changes in NF-κB nuclear import or distribution. While colocalizing with ASC in perinuclear specks, POP2 also inhibits the formation of specks by the CLR protein CIAS1 / NALP3. Together these observations indicate that POP2 is a
negative regulator of NF-KB activity that may influence the
assembly of pyrin-domain dependent complexes.