NALPs: a novel protein family involved in inflammation

Abstract

On infection, microorganisms are efficiently recognized by Toll-like receptors (TLRs), which recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) that are shared by many pathogens but are not expressed by their hosts. Recognition of PAMPs by TLRs results in the activation of different intracellular signalling cascades, which, in turn, lead to the expression of various effector molecules. One of these, interleukin-1β (IL-1β), is defined as an 'alarm cytokine'; it is secreted by macrophages and initiates inflammation. For IL-1β to be active, pro-IL-1β must first be processed to an active molecule and then secreted. The IL-1β-converting enzyme (ICE) — also known as caspase-1 — is responsible for this processing. A novel family of cytoplasmic proteins containing NACHT, leucine-rich domains and either a Pyrin or CARD domain are involved in caspase-1 activation and therefore IL-1β cleavage. One member of this family, designated NALP1, assembles into a complex with ASC, caspase-1 and caspase-5, forming the 'inflammasome'. The NALP3 gene is mutated in three related autosomal-dominant autoinflammatory disorders, Muckle–Wells syndrome, familial cold urticaria, and in chronic infantile neurologic cutaneous and articular syndrome.