Small ISGs Coming Forward

Abstract

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/Leu13, 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.

Expression of the mouse fragilis gene products in immune cells and association with receptor signaling complexes

“…2 Accordingly, in Figure 2b, transcripts are shown from total bone marrow (BM), bone marrow derived macrophages (BMMf) and bone marrow derived MMC treated with IFN-b. Similar to the preceding data, a wide variety of fragilis genes are transcriptionaly active in such cell types; however, responses to interferon treatment were muted.…”

“…1 The fragilis genes are highly homologous to a similar family of genes in the human (the Ifitm family) that possesses at least four members, including Ifitm1, which is also known as Leu-13 and 9-27. 2 The production of monoclonal antibodies against the Leu-13 protein has allowed extensive studies on the functions of the protein. 3,4 Multiple members of this gene family have been found in other vertebrate species studied including four such genes in the rat, 2,5,6 at least two in the cow 6,7 and one in the electric torpedo ray.…”

“…2 The production of monoclonal antibodies against the Leu-13 protein has allowed extensive studies on the functions of the protein. 3,4 Multiple members of this gene family have been found in other vertebrate species studied including four such genes in the rat, 2,5,6 at least two in the cow 6,7 and one in the electric torpedo ray. 8 The Leu-13 protein has been functionally defined as contributing to cell-to-cell homotypic adhesions, 4,9,10 depressing proliferation, 4,[11][12][13] and modulating cell activation.…”

Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

“…Although these pathways are activated independently of each other and mTOR inhibition does not affect the formation of STAT complexes and gene transcription (23,24), it appears that they cooperate in the control of common biological responses via regulation of expression of common protein mediators. For instance, it is well established that the promoter of the Isg15 gene contains three ISRE elements and that the STAT pathway regulates its transcriptional activation (50). In fact, the original definition of ISREs was based on their identification and description of their presence in the Isg15 gene promoter (50,51).…”

“…For instance, it is well established that the promoter of the Isg15 gene contains three ISRE elements and that the STAT pathway regulates its transcriptional activation (50). In fact, the original definition of ISREs was based on their identification and description of their presence in the Isg15 gene promoter (50,51). Our findings now provide direct evidence that translational control of the Isg15 gene product is regulated by cap-dependent translation, as evidenced by the enhanced up-regulation of IFN␣-dependent ISG15 protein expression in cells with targeted disruption of the 4e-bp1 gene.…”