A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence.

Abstract

Interleukin 1 (IL‐1) is a major soluble mediator of inflammation. Two human IL‐1 genes, alpha and beta, have been isolated, which encode polypeptides with only 20‐30% amino acid sequence homology. Unlike most secreted proteins, the two cytokines do not have a signal sequence, an unexpected finding in view of their biological role. Here we show that IL‐1 beta is actively secreted by activated human monocytes via a pathway of secretion different from the classical endoplasmic reticulum‐‐Golgi route. Drugs which block the intracellular transport of IL‐6, of tumour necrosis factor alpha and of other secretory proteins do not inhibit secretion of IL‐1 beta. Secretion of IL‐1 beta is blocked by methylamine, low temperature or serum free medium, and is increased by raising the culture temperature to 42 degrees C or by the presence of calcium ionophores, brefeldin A, monensin, dinitrophenol or carbonyl cyanide chlorophenylhydrazone. IL‐1 beta is contained in part within intracellular vesicles which protect it from protease digestion. In U937 cells large amounts of IL‐1 beta are made but none is secreted. In these cells IL‐1 beta is not found in the vesicular fraction, and all the protein is accessible to protease digestion. This suggests that intracellular vesicles that contain IL‐1 beta are part of the protein secretory pathway. We conclude that IL‐1 beta is released by activated monocytes via a novel mechanism of secretion which may involve translocation of intracellular membranes and is increased by stress conditions.

Intercellular trafficking of VP22-GFP fusion proteins is not observed in cultured mammalian cells

“…Lysosomal enzymes, for example, are secreted from and re-enter cells by mannose-6-phosphate-mediated pathways. 8 With few exceptions 9,10 secretory proteins are translocated across the endoplasmic reticulum (ER) membrane during their synthesis. Such translocation is mediated by a hydrophobic signal sequence, a signal recognition protein (SRP), and an SRP receptor (docking protein) located in the ER.…”

Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

“…IL-1β precursors do not have a clear signal peptide for synthesis and secretion and none of them is found in the Golgi [3]. So IL-1β belongs to a so-called leaderless secretory protein group lacking a secretory signal sequence.…”

Correlation of polymorphic variation in the promoter region of the interleukin‐1β gene with secretion of interleukin‐1β protein

“…IL-1␤ is produced as a 31-kd precursor protein and belongs to a class of leaderless proteins that lack signal peptides (4)(5). It requires cleavage by caspase 1 to produce its active form (6) and its secretory pathway has not yet been fully characterized, although externalization occurs through a mechanism that is independent of the rough endoplasmic reticulum and golgi apparatus (7).…”