Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF‐κB and caspase‐1

Abstract

PYRIN-containing Apaf-1-like proteins (PYPAFs) are a recently identi¢ed family of proteins thought to function in apoptotic and in£ammatory signaling pathways. PYPAF1 and PYPAF7 proteins have been found to assemble with the PYRIN^CARD protein ASC and coordinate the activation of NF-U UB and pro-caspase-1. To determine if other PYPAF family members function in pro-in£ammatory signaling pathways, we screened ¢ve other PYPAF proteins (PYPAF2, PYPAF3, PY-PAF4, PYPAF5 and PYPAF6) for their ability to activate NF-U UB and pro-caspase-1. Co-expression of PYPAF5 with ASC results in a synergistic activation of NF-U UB and the recruitment of PYPAF5 to punctate structures in the cytoplasm. The expression of PYPAF5 is highly restricted to granulocytes and T-cells, indicating a role for this protein in in£ammatory signaling. In contrast, PYPAF2, PYPAF3, PYPAF4 and PYPAF6 failed to colocalize with ASC and activate NF-U UB. PYPAF5 also synergistically activated caspase-1-dependent cytokine processing when co-expressed with ASC. These ¢ndings suggest that PYPAF5 functions in immune cells to coordinate the transduction of pro-in£ammatory signals to the activation of NF-U UB and pro-caspase-1.

Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data

“…B-cell-specific gene NALP7 (Supplementary Figure 3b) is a member of a family of pyrin domain proteins with some members implicated in inflammatory signalling. 68 LOC220213 is in only bone marrow plasma cells and FLJ23235 is also expressed in plasma cells from blood. KIAA1384 is specifically and highly expressed only in blood plasma cells (Figure 3c).…”

TIR, CARD and PYRIN: three domains for an antimicrobial triad

“…41 For most of them, the function of Nalps remains unknown. Two Nalp family members, Nalp6 (Pypaf5) 120 and Nalp12 (Pypaf7 or Monarch-1) 121 have been shown to activate the NF-kB pathway. However, others have reported that Monarch-1 dampens NF-kB signals triggered by TLRs or TNF stimulation.…”

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

“…A more recent proposal suggests the name NACHT-LRR or NLR [9]. Several others reported on the pyrin-containing subgroup or members of this subgroup, which were given various names including PAN, PYPAF and NALP [10][11][12].…”