Pyrin-only protein 2 modulates NF-kappaB and disrupts ASC:CLR interactions.
NF-kappaB 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 domains have roles in apoptosis, innate immunity, and inflammation. Many pyrin domain (PYD) proteins modulate NF-kappaB activity as well as participate in assembling both the perinuclear "apoptotic speck" and the pro-IL1beta/IL-18-converting inflammasome complex. "Pyrin-only" proteins (POP) are attractive as negative regulators of PYD-mediated functions and one such protein, POP1, has been reported. We report the identification and initial characterization of a second POP. POP2 is a 294 nt single exon gene located on human chromosome 3 encoding a 97-aa protein with sequence and predicted structural similarity to other PYDs. Highly similar to PYDs in CATERPILLER (CLR, NLR, NALP) family proteins, POP2 is less like the prototypic pyrin and ASC PYDs. POP2 is expressed principally in peripheral blood leukocytes and displays both cytoplasmic and nuclear expression patterns in transfected cells. TNF-alpha-stimulated and p65 (RelA)-induced NF-kappaB-dependent gene transcription is inhibited by POP2 in vitro by a mechanism involving changes in NF-kappaB 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 demonstrate that POP2 is a negative regulator of NF-kappaB activity that may influence the assembly of PYD-dependent complexes.
Bedoya
Felipe
F
Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Sandler
Laurel L
LL
Harton
Jonathan A
JA
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019556:COS Cells; D058286:Calcitonin Receptor-Like Protein; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D018003:Receptors, Calcitonin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C545578:CALCRL protein, human; C489780:CNOT8 protein, human; D058286:Calcitonin Receptor-Like Protein; D018797:Cell Cycle Proteins; C485678:DBF4 protein, human; D046912:Multiprotein Complexes; D016328:NF-kappa B; C490350:POP1 protein, human; C498143:RELA protein, human; D018003:Receptors, Calcitonin; D012261:Ribonucleoproteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1