Fig. 9.

Schematic diagram depicting the proposed signaling pathway involved in interferon-induced transmembrane protein 1 (IFITM1) upregulation in SUM149 cells. IFITM1 is one of the interferon-stimulated genes (ISGs) that are induced through the canonical Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway due to increased expression of interferon α (IFNα). The binding of IFNα to its receptor interferon (alpha, beta and omega) receptor (IFNAR1/2) leads to the induction of the canonical JAK-STAT pathway, which involves phosphorylation of STAT1, STAT2, and the formation of the complex interferon-stimulated gene factor 3 (ISGF3), ultimately inducing many ISGs, including IFITM1. In the nucleus, ISGF3 recruits chromatin remodeling complex brahma-related gene 1 (BRG1) via STAT2 to remodel the promoter and expose interferon-stimulated response element (ISRE)/interferon gamma-activated site (GAS) for transcription factor binding. Alternatively, STAT2 can homodimerize upon phosphorylation, and bind interferon regulatory factor 9 (IRF9) to form a non-ISGF3 complex that is capable of binding the GAS or ISRE/IRF sequences at the promoter region of a subset of ISGs and induce their transcription without the participation of STAT1 in a noncanonical interferon signaling pathway. The presence of both GAS and ISRE/IRF consensus sequences at the IFITM1 promoter suggests that its transcription can be induced by both canonical and noncanonical signaling pathways, resulting in its overexpression in SUM149 cells