IFITM1 explained

Interferon-induced transmembrane protein 1 is a protein that in humans is encoded by the IFITM1 gene.^{[1] [2]} IFITM1 has also recently been designated CD225 (cluster of differentiation 225). This protein has several additional names: fragilis (human homolog of the mouse protein), IFI17 [interferon-induced protein 17], 9-27 [Interferon-inducible protein 9-27] and Leu13.

IFITM1 is a member of the IFITM family (Interferon-induced transmembrane protein) which is encoded by IFITM genes. The human IFITM genes locate on chromosome 11 and have four members: IFITM1, IFITM2, IFITM3 and IFITM5.^[3] While the mouse Ifitm genes locate on chromosome 7 and 16 and have six members: Ifitm1, Ifitm2, Ifitm3, Ifitm5, Ifitm6 and Ifitm7.

Molecular biology

The IFITM1 gene is located on the Watson (plus) strand of the short arm of chromosome 11 (11p15.5) and is 3,956 bases in length. The encoded protein has 125 amino acids (molecular weight 13.964 kDa).

It is an intrinsic membrane protein and is predicted to cross the membrane several times.

Structure and function

IFITM proteins have a short N-terminal and C-terminal domain, two transmembrane domains (TM1 and TM2) and a short cytoplasmic domain. The first transmembrane domain (TM1) and the cytoplasmic domain are conserved among different IFITM proteins in humans and mice.^[4] In the absence of interferon stimulation, IFITM proteins can express broadly in tissues and cell lines. In humans, IFITM1, IFITM2 and IFITM3 are able to express in different tissues and cells while the expression of IFITM5 is limited to osteoblasts.^[5] The type I and II interferon induce IFITM proteins expression significantly. IFITM proteins are involved in the physiological process of immune response signaling, germ cell maturation and development.^[6]

Biochemistry

The gene is induced by interferon and the protein forms part of the signaling pathway.

Antiviral function of IFITM proteins

IFITM proteins have been identified as cell-autonomous proteins that suppress the early stages of viral replication.^[7] Knockout of IFITM3 increased influenza A virus replication, and overexpression of IFITM3 inhibits influenza virus A replication.^[8] In addition to replication competent influenza A virus, IFITM proteins were able to inhibit retrovirus based pseudotyped influenza A virus, indicating that IFITM protein inhibit influenza A virus at the early step of life cycle, may occur in the entry and fusion steps.

IFITM proteins also are able to inhibit several infection with other enveloped viruses that belong to different virus families. These virus include flaviviruses (dengue virus and West Nile virus), filoviruses (Marburg virus and Ebola virus), coronaviruses (SARS coronavirus) and lentiviruses (Human Immunodeficiency Virus (HIV)).^[9] However, IFITM proteins did not affect alphavirus, arenavirus, or murine leukaemia virus infection.

IFITM proteins inhibit viral membrane and cellular endosomal or lysosomal vesicle membrane fusion by modifying their lipid components or fluidity. IFITM proteins block the hemifusion stage of entry,^[7] an intermediate stage in which portions the outer membranes of the target cell and the viral envelope mix prior to completion of fusion.^[10] Furthermore, IFITM proteins reduced membrane fluidity and affected membrane curvature to restrict viral membrane fusion with the cellular membrane.^[7] In addition, IFITM3 interacted with the cellular cholesterol regulatory proteins vesicle associated membrane protein A (VAPA) and oxysterol binding protein (OSBP) to induce intracellular cholesterol accumulation, which in turn blocks viral membrane and vesicle membrane fusion.^[11]

Further reading

• Bradbury LE, Kansas GS, Levy S, etal . The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. . J. Immunol. . 149 . 9 . 2841–50 . 1992 . 10.4049/jimmunol.149.9.2841 . 1383329 . 23655762 . free .
• Takahashi S, Doss C, Levy S, Levy R . TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen. . J. Immunol. . 145 . 7 . 2207–13 . 1990 . 10.4049/jimmunol.145.7.2207 . 2398277 . 30999229 . free .
• Reid LE, Brasnett AH, Gilbert CS, etal . A single DNA response element can confer inducibility by both alpha- and gamma-interferons. . Proc. Natl. Acad. Sci. U.S.A. . 86 . 3 . 840–4 . 1989 . 2492664 . 10.1073/pnas.86.3.840 . 286573 . 1989PNAS...86..840R . free .
• Kelly JM, Gilbert CS, Stark GR, Kerr IM . Differential regulation of interferon-induced mRNAs and c-myc mRNA by alpha- and gamma-interferons. . Eur. J. Biochem. . 153 . 2 . 367–71 . 1986 . 3935435 . 10.1111/j.1432-1033.1985.tb09312.x . free .
• Friedman RL, Manly SP, McMahon M, etal . Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. . Cell . 38 . 3 . 745–55 . 1984 . 6548414 . 10.1016/0092-8674(84)90270-8 . 37810920 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Kita K, Sugaya S, Zhai L, etal . Involvement of LEU13 in interferon-induced refractoriness of human RSa cells to cell killing by X rays. . Radiat. Res. . 160 . 3 . 302–8 . 2003 . 12926988 . 10.1667/RR3039 . 2003RadR..160..302K . 34613110 .
• Lehner B, Semple JI, Brown SE, etal . Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region. . Genomics . 83 . 1 . 153–67 . 2004 . 14667819 . 10.1016/S0888-7543(03)00235-0 .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Akyerli CB, Beksac M, Holko M, etal . Expression of IFITM1 in chronic myeloid leukemia patients. . Leuk. Res. . 29 . 3 . 283–6 . 2005 . 15661263 . 10.1016/j.leukres.2004.07.007 . 11693/24093 . 43389978 . free .
• Yang Y, Lee JH, Kim KY, etal . The interferon-inducible 9-27 gene modulates the susceptibility to natural killer cells and the invasiveness of gastric cancer cells. . Cancer Lett. . 221 . 2 . 191–200 . 2005 . 15808405 . 10.1016/j.canlet.2004.08.022 .
• Rual JF, Venkatesan K, Hao T, etal . Towards a proteome-scale map of the human protein-protein interaction network. . Nature . 437 . 7062 . 1173–8 . 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .

Notes and References

1. Deblandre GA, Marinx OP, Evans SS, Majjaj S, Leo O, Caput D, Huez GA, Wathelet MG . Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth . J Biol Chem . 270 . 40 . 23860–6 . Nov 1995 . 7559564 . 10.1074/jbc.270.40.23860 . free .
2. Web site: Entrez Gene: IFITM1 interferon induced transmembrane protein 1 (9-27).
3. Hickford D, Frankenberg S, Shaw G, Renfree MB . Evolution of vertebrate interferon inducible transmembrane proteins . BMC Genomics . 13 . 155 . 2012 . 22537233 . 3424830 . 10.1186/1471-2164-13-155 . free .
4. Yount JS, Moltedo B, Yang YY, Charron G, Moran TM, López CB, Hang HC . Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3 . Nat. Chem. Biol. . 6 . 8 . 610–4 . August 2010 . 20601941 . 2928251 . 10.1038/nchembio.405 .
5. Tanaka SS, Yamaguchi YL, Tsoi B, Lickert H, Tam PP . IFITM/Mil/fragilis family proteins IFITM1 and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion . Dev. Cell . 9 . 6 . 745–56 . December 2005 . 16326387 . 10.1016/j.devcel.2005.10.010 . free .
6. Lewin AR, Reid LE, McMahon M, Stark GR, Kerr IM . Molecular analysis of a human interferon-inducible gene family . Eur. J. Biochem. . 199 . 2 . 417–23 . July 1991 . 1906403 . 10.1111/j.1432-1033.1991.tb16139.x. free .
7. Li K, Markosyan RM, Zheng YM, Golfetto O, Bungart B, Li M, Ding S, He Y, Liang C, Lee JC, Gratton E, Cohen FS, Liu SL . IFITM proteins restrict viral membrane hemifusion . PLOS Pathog. . 9 . 1 . e1003124 . January 2013 . 23358889 . 3554583 . 10.1371/journal.ppat.1003124 . free .
8. Feeley EM, Sims JS, John SP, Chin CR, Pertel T, Chen LM, Gaiha GD, Ryan BJ, Donis RO, Elledge SJ, Brass AL . IFITM3 inhibits influenza A virus infection by preventing cytosolic entry . PLOS Pathog. . 7 . 10 . e1002337 . October 2011 . 22046135 . 3203188 . 10.1371/journal.ppat.1002337 . free .
9. Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ . The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus . Cell . 139 . 7 . 1243–54 . December 2009 . 20064371 . 2824905 . 10.1016/j.cell.2009.12.017 .
10. Harrison . Stephen C . Viral membrane fusion . Nat Struct Mol Biol . July 2008 . 15 . 7 . 690–8 . 10.1038/nsmb.1456 . 18596815 . 2517140 .
11. Amini-Bavil-Olyaee S, Choi YJ, Lee JH, Shi M, Huang IC, Farzan M, Jung JU . The Antiviral Effector IFITM3 Disrupts Intracellular Cholesterol Homeostasis to Block Viral Entry . Cell Host Microbe . 13 . 4 . 452–64 . April 2013 . 23601107 . 10.1016/j.chom.2013.03.006 . 3646482.