Pyrin-Only Protein 2 Modulates NF-κB and Disrupts ASC:CLR Interactions

Abstract

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 domains have roles in apoptosis, innate immunity, and inflammation. Many pyrin domain (PYD) proteins modulate NF-κB activity as well as participate in assembling both the perinuclear “apoptotic speck” and the pro-IL1β/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-α-stimulated and p65 (RelA)-induced NF-κB-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 demonstrate that POP2 is a negative regulator of NF-κB activity that may influence the assembly of PYD-dependent complexes.

Inflammasomes and its importance in viral infections

“…Thus, POP1 prevents inflammasome activation by obstructing ASC assembly, resulting in the inhibition of caspase-1 activation as well as IL-1b and IL-18 secretion, and weak nucleation of ASC polymerisation [118]. Another POP family member, called POP2, blocks TNF-a-mediated NF-jB activation [122]. POP2 acts distally in the NF-jB cascade by regulating the transactivation potential of the C-terminal transcriptional activation domain 1 of p65/RelA [123].…”

Strategies that modulate inflammasomes—insights from host–pathogen interactions

“…The structurally similar cPOP2 is expressed primarily in peripheral blood leukocytes. Unlike cPOP1, cPOP2 more closely aligns with the PYD-NLRs than ASC [9]. As a result, cPOP-2 has been shown to bind to the PYD of both ASC and several PYD-NLR proteins, including NALP3 and PAN1, to impair inflammasome-mediated activation of pro-caspase-1 and IL-1β processing [9].…”

“…Unlike cPOP1, cPOP2 more closely aligns with the PYD-NLRs than ASC [9]. As a result, cPOP-2 has been shown to bind to the PYD of both ASC and several PYD-NLR proteins, including NALP3 and PAN1, to impair inflammasome-mediated activation of pro-caspase-1 and IL-1β processing [9]. Like cPOP1, cPOP2 has been shown to inhibit activation of NF-κBi n response to cytokine stimulation [9], indicating that cPOP2 functions as a negative regulator of diverse innate immune and inflammatory responses.…”

“…As a result, cPOP-2 has been shown to bind to the PYD of both ASC and several PYD-NLR proteins, including NALP3 and PAN1, to impair inflammasome-mediated activation of pro-caspase-1 and IL-1β processing [9]. Like cPOP1, cPOP2 has been shown to inhibit activation of NF-κBi n response to cytokine stimulation [9], indicating that cPOP2 functions as a negative regulator of diverse innate immune and inflammatory responses. Thus, the presence of cPOPs and their ability to regulate ASC interactions have broad implications for cellular development, survival, and homeostasis.…”

“…As such, POPs may have applications in dampening adverse inflammatory processes by blocking pro-inflammatory signal upstream and downstream of the inflammasome complex, impeding inflammasome assembly or limiting the duration of inflammasomes. For example, cPOP2 has been shown to disrupt the NALP3 inflammasome [9]. Given the number of pathologies attributed to excessive and uncontrolled NALP3 activity, therapies built on the premise of increasing cPOP2 expression and/or activity may be useful in the treatment of multiple conditions.…”