Fig. 2

IFITM proteins are involved in various cellular processes with direct and indirect impacts on immunity. Virus restriction; In the event of successful virus invasion, nucleic acid sensors including RIG-I and MDA5 are triggered and IRF transcription factors are activated to induce the production of type-I interferons, which, in turn, initiate transcription of IFITM genes and other interferon-stimulated genes. IFITM proteins restrict the cytosolic access of virions undergoing endocytosis, possibly via inhibition of virus-cell fusion and destruction in an endolysosomal pathway. Cytokine regulation; IFITM3 is a negative regulator of the interferon response because it accelerates the turnover of IRF3 in autophagosomes. It also suppresses the production of IL-6, a pro-inflammatory cytokine which, itself, can also induce the expression of IFITM genes. IFITM2, in contrast, promotes the upregulation of IL-6 by acting as a cell surface receptor for secreted BAG3. As BAG3 is also a well-characterized chaperone for selective autophagy, it will be of interest to determine if IFITM2 also participates with BAG3 in autophagy-related processes. Cell migration and invasion; IFITM3 is a central component of a multi-protein interaction involving Src, FAK, and Ambra1, which is important for regulating cell adhesion and movement. IFITM3 assists in the subcellular trafficking of Src between focal adhesion points and autophagosomes. Cell growth, proliferation, and cell cycle regulation; Interferon signaling is known to negatively regulate cell division and growth via STAT signaling, with IFITM proteins serving as downstream effectors. IFITM1 interacts with caveolin-1 (CAV-1) to inhibit ERK/MAPK signaling, a pathway which stimulates cell proliferation when active. IFITM1 also stabilizes p53, a tumor suppressor with anti-proliferative functions