PYPAF3, a PYRIN-containing APAF-1-like Protein, Is a Feedback Regulator of Caspase-1-dependent Interleukin-1β Secretion

Abstract

PYPAF3 is a member of the PYRIN-containing apoptotic protease-activating factor-1-like proteins (PYPAFs, also called NALPs). Among the members of this family, PYPAF1, PYPAF5, PYPAF7, and NALP1 have been shown to induce caspase-1-dependent interleukin-1␤ secretion and NF-B activation in the presence of the adaptor molecule ASC. On the other hand, we recently discovered that PYNOD, another member of this family, is a suppressor of these responses. Here, we show that PYPAF3 is the second member that inhibits caspase-1-dependent interleukin-1␤ secretion. In contrast, PYPAF2/NALP2 does not inhibit this response but rather inhibits the NF-B activation that is induced by the combined expression of PYPAF1 and ASC. Both PYPAF2 and PYPAF3 mRNAs are broadly expressed in a variety of tissues; however, neither is expressed in skeletal muscle, and only PYPAF2 mRNA is expressed in heart and brain. They are also expressed in many cell lines of both hematopoietic and non-hematopoietic lineages. Stimulation of monocytic THP-1 cells with lipopolysaccharide or interleukin-1␤ induced PYPAF3 mRNA expression. Furthermore, the stable expression of PYPAF3 in THP-1 cells abrogated the ability of the cells to produce interleukin-1␤ in response to lipopolysaccharide. These results suggest that PYPAF3 is a feedback regulator of interleukin-1␤ secretion. Thus, PYPAF2 and PYPAF3, together with PYNOD, constitute an anti-inflammatory subgroup of PYPAFs.

NLRP2, an Inhibitor of the NF-κB Pathway, Is Transcriptionally Activated by NF-κB and Exhibits a Nonfunctional Allelic Variant

“…Previous studies showed that NLRP2 is broadly expressed in tissues and tumor cell lines (6,15). In this study, we report that NLRP2 is up-regulated during differentiation of hemopoietic and mesenchymal progenitors.…”

“…Initial studies showed that NLRP2 is widely expressed in tissues and tumor cell lines (6,15). However, the expression of NLRP2 in progenitor cells and its regulation during differentiation of these progenitors is not known.…”

Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions

“…Similar to PYAF2, PYPAF3 is broadly expressed and induced by LPS or proinflammatory cytokines [29]. However, in contrast to PYPAF2, PYPAF3 has no measured effect on NF-κB activation.…”

“…PYPAF2 is expressed more broadly than CLR16.2 or Monarch-1 and mRNA can be detected in many different cell types and tissues, including non-hematopoietic cells [19,29]. In addition, distinct from Monarch-1 and CLR16.2, PYPAF2 expression is induced following treatment of cells with LPS or proinflammatory cytokines.…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…92,93 Mutations in NLRP7 have mainly been Genetics of the inflammasomes in human pathologies C Conforti-Andreoni et al 140 associated with aberrant development of the reproductive tract, such as endometrial cancer tissues and familial recurrent hydatidiform moles. 94 Mutations in genes encoding pyrin and proline-serine-threonine phosphatase-interacting protein 1 are associated with two autoinflammatory diseases with hereditary periodic fever syndrome-like symptoms: familial mediterranean fever and pyogenic arthritis pyoderma gangrenosum and acne syndrome, respectively.…”