The invention provides isolated nucleic acid molecules encoding PAAD-domain containing polypeptides and functional fragments thereof, including fragments containing PAAD domains, NACHT domains and ARED domains, encoded polypeptides, and antibodies. Also provided are methods of identifying polypeptides and agents that associate with a PAAD-domain containing polypeptide or fragment thereof, or that alter an association of a PAAD domain-containing polypeptides. Further provided are methods of identifying agents that modulate PAAD domain-mediated inhibition of NFKB activity, or modulate an activity of a NACHT domain of a PAAD domain-containing polypeptide. Also provided are methods of modulating NFKB transcriptional activity in a cell, and methods of altering expression of a PAAD domain-containing polypeptide in a cell.