8.A.58.1.3
IFITM3 or IFM3 of 133 aas and 2 TMSs, one at  residies 60 80, and one C-terminal.  It participates in the defense against viral infections (López-Jiménez et al. 2018). It plays a role in the structural stability and function of vacuolar ATPase (V-ATPase), establishing physical contact with the V-ATPase of endosomes which is required for the function of the V-ATPase to lower the pH in phagocytic endosomes, thus establishing an antiviral state (Brass et al. 2009).  IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry, underscoring the importance of cholesterol in virus infection (Amini-Bavil-Olyaee et al. 2013). The palmitoyltransferase ZDHHC20 enhances IFITM3 palmitoylation and antiviral activity (McMichael et al. 2017).  mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3 (Shi et al. 2018). IFITM3 directly engages and shuttles incoming viruses to lysosomes.  This trafficking is specific to restricted viruses, requires S-palmitoylation and is abrogated in loss-of-function mutants (Spence et al. 2019). Residues F75 and F78 are critical for antiviral activity, but these residues are dispensable for IFITM3 membrane localization and IFITM3/IFITM3 interactions (Winkler et al. 2019). IFITM3 reduces retroviral envelope abundance and function and is counteracted by glycoGag (Ahi et al. 2020). IFITM3 trafficking and turnover are regulated  by the VCP/p97 ATPase (Wu et al. 2020). IFN-induced antiviral protein disrupts intracellular cholesterol homeostasis and inhibits the entry of viruses to the host cell cytoplasm by preventing viral fusion with cholesterol depleted endosomes. It may inactivate new enveloped viruses which bud out of the infected cell, by letting them go out with a cholesterol depleted membrane. It is active against multiple viruses, including influenza A virus, SARS coronaviruses (SARS-CoV and SARS-CoV-2), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and vesicular stomatitis virus (VSV) (Narayana et al. 2015, Shi et al. 2021, Zang et al. 2020). IFITM3 is an NTCP co-factor that affects infection with hepatitis B and D viruses (HBV and HDV) in NTCP-expressing hepatoma cells. A direct interaction (PPI) between IFITM3 and NTCP has been demonstrated (Palatini et al. 2022). Cholesterol binds the amphipathic helix of IFITM3 to regulate its antiviral activity (Rahman et al. 2022). IFITM proteins broadly inhibit the entry of diverse pathogenic viruses, including Influenza A virus (IAV), Zika virus, HIV-1, and SARS coronaviruses by inhibiting virus-cell membrane fusion (Rahman et al. 2022). Inhibition of IAV entry by IFITM3 is associated with its ability to promote cellular membrane rigidity via the amphipathic helix found in the intramembrane domain (IMD) of IFITM3. The IFITM-3 (rs12252) variant is involved in HIV-1 mother-to-child transmission susceptibility (Leandro et al. 2023). IFITM1 enhances nonenveloped viral RNA replication by facilitating cholesterol transport to the Golgi (Ishikawa-Sasaki et al. 2023). IFITM3 blocks influenza virus entry by sorting lipids and stabilizing hemifusion (Klein et al. 2023).  Interferon-induced transmembrane proteins (IFITM) modulate cell permeability of diverse linked chemotypes (PMID 36546854).  IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma (Jeong et al. 2024).