Intracellular interleukin (IL)-1 family cytokine processing enzyme

The interleukin (IL)-1 family is the largest family of interleukins. Eleven members of the IL-1 family of ligands are intracellular molecules, except a single isoform of an IL-1 receptor antagonist (IL-1Ra; also known as IL-1RN), which contains a signal peptide at the N-terminus for effective secretion. The inflammasome is a complex of intracellular molecules that is responsible for the processing of IL-1β and IL-18, whereas the remaining IL-1 family members, including IL-1α, are processed in an inflammasome caspase-1-independent pathway. Among the eleven members of the IL-1 family ligands, precursor IL-1α, IL-1β, and IL-33 have comparatively long pro-peptides of approximately 110 amino acid residues at the N-terminus. However, the other IL-1 members, except for IL-37 (also known as IL-1F7), have relatively short propeptides with fewer than 40 amino acid residues at the N-terminus. Most cytokines, including interferons and interleukins, possess a hydrophobic signal sequence for secretion. Therefore, soluble cytokines readily act on cell surface receptors immediately after their release from cells. Unlike other cytokine families, IL-1 family ligands exhibit two-step regulation: transcriptional induction at the mRNA level and post-translational modification at the protein level because of the lack of a hydrophobic signal sequence at the N-terminus. Various processing enzymes involved in the activation of intracellular IL-1 family cytokines likely provide effective immune regulation to protect the host from infections. In this review, we describe all eleven IL-1 family ligand processing enzymes, mature ligand functions, and mode of receptor conformation.