Ubiquitin-like proteins fall into two classes: the first class, ubiquitin-like modifiers (UBLs) function as modifiers in a manner analogous to that of ubiquitin. Examples of UBLs are SUMO, Rub1 (also called Nedd8), Apg12, Hub1. Proteins of the second class include parkin, RAD23 and DSK2, are designated ubiquitin-domain proteins (UDPs). These proteins contain domains that are related to ubiquitin but are otherwise unrelated to each other. In contrast to UBLs, UDPs are not proteolytically processed or conjugated to other proteins. ISG15 (Interferon Stimulating Gene-15) shows no amino acid sequence homology to cytokines and is synthesized as a precursor that is activated through processing by a thiol protease. ISG15 is secreted by monocytes and lymphocytes. Synthesis is induced in response to IFN-a or IFN-b or IFN-a, but not IFN-g. ISG15 expression is induced also by overexpression of some interferon regulatory factors that have been shown to play a role in the transcriptional regulation of IFN genes. ISG15 is secreted also by cell lines of monocyte (U937 cell line), T-lymphocyte, B-lymphocyte (DAUDI cells), human fibroblasts, and epithelial origins. The induction of terminal differentiation in human melanoma cells is associated, among other things, with alterations in the expression of ISG15. Intracellularly ISG15 has been shown to function as a ubiquitin homologue. It is known also as UCRP (ubiquitin cross-reactive protein). Serpin 2a (spi2a), a member of the serine protease inhibitor (serpin) protein family that is highly induced in macrophages during bacillus Calmette-Guerin infection has been shown to bind ISG15. ISG15 has been shown to modulate immune cell function. It possesses activities of cytokines and induces production of IFN-g. It enhances proliferation and functions of natural killer and LAK cells.