Small ISGs coming forward

Interferons (IFNs) were first characterized as antiviral proteins. Since then, IFNs have proved to be involved in malignant, angiogenic, inflammatory, immune, and fibrous diseases and, thus, possess a broad spectrum of pathophysiologic properties. IFNs activate a cascade of intracellular signaling pathways leading to upregulation of more than 1000 IFN-stimulated genes (ISGs) within the cell. The function of some of the IFN-induced proteins is well described, whereas that of many others remain poorly characterized. This review focuses on three families of small intracellular and intrinsically nonsecreted proteins (10-20 kDa) separated into groups according to their amino acid sequence similarity: the ISG12 group (6-16, ISG12, and ISG12-S), the 1-8 group (9-27/Leu-13, 1-8U, and 1-8D), and the ISG15 group (ISG15/UCRP). These IFN-induced genes are abundantly and widely expressed and mainly induced by type I IFN. ISG15 is very well described and is a member of the ubiquitin-like group of proteins. 9-27/Leu-13 associates with CD81/TAPA-1 and plays a role in B cell development. The functions of 1-8U, 1-8D, 6-16, ISG12, and ISG12-S proteins are unknown at present.