GXXXG motifs and aromatic amino acids are common features of the transmembrane domains of many different plasma membrane proteins with GXXXG motifs most often located at the N-terminus [55, 56, 57] and Y/F/W aromatic amino acids at the C-terminus of the transmembrane domain [58, 59] . Many of the proteins also have Sternberg-Gullick dimerization motifs, a family of sequences discovered in the transmembrane domain of tyrosine kinase growth factor receptors [60] . Members of this family, which includes a subset of GXXXG/AXXXG/SXXXG dimerization motifs, are composed of 5 amino acids arranged with G, A, S, T or P in the first position (N-terminus), an A, V, L or I in the fourth position and G or A in the fifth position. Our findings demonstrate that a single amino acid substitution in the transmembrane domain of CEACAM1-4S can produce dramatic effects on cell proliferation, anchorage independent growth and in vivo tumorigenicity. It seems clear that the transmembrane domain and more specifically GXXXG motifs and tyrosine residues make a significant contribution to the functionality of CEACAM1-4S and by extension, to other transmembrane proteins with similar characteristics. Further studies are needed to define the downstream signaling events impacted by re-expression of CEACAM1-4S or by transmembrane domain mutations, studies that should provide valuable insights into events controlled by transmembrane domain mediated interactions. Of particular interest will be the identity of pathways inactivated/activated by tyrosine mutations that lead to the positive growth effects of tyrosine mutations and the ability of these pathways to counteract the tumor suppressor activity of CEACAM1-4L, the larger splice variant with the same transmembrane domain as the 4S isoform. Human Subtilase SKI-1/S1P Is a Master Regulator of the HCV Lifecycle and a Potential Host Cell Target for Developing Indirect-Acting Antiviral Agents HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1) – or site-1 protease (S1P). SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI-1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP)/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF-429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow development of novel broad-spectrum biopharmaceuticals that could lead to novel indirect-acting antiviral options with the current standard of care. Hijacking of host lipids and their biosynthetic pathways is a common strategy for microbial infection. Human enveloped viruses including hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-1 use cholesterol-rich lipid rafts for entry [1, 2] , assembly [3] , and/or replication [2, 4] . Lipid droplets (LDs), once considered static storage vesicles for host lipids, are now appreciated as dynamic organelles [5] that are also utilized in the lifecycles of pathogenic human viruses including rotavirus (RV) [6] , dengue virus (DV) [7] , and HCV [8] . HCV in particular requires host LDs for assembly of nascent viral particles [9] [10] [11] .