IFITM-Family Proteins: The Cell's First Line of Antiviral Defense

Overview

Journal Annu Rev Virol

Publisher Annual Reviews

Specialty Microbiology

Date 2015 Jan 20

PMID 25599080

Citations 286

Authors

Charles C Bailey

Guocai Zhong

I-Chueh Huang

Michael Farzan

Affiliations

Soon will be listed here.

Abstract

Animal cells use a wide variety of mechanisms to slow or prevent replication of viruses. These mechanisms are usually mediated by antiviral proteins whose expression and activities can be constitutive but are frequently amplified by interferon induction. Among these interferon-stimulated proteins, members of the IFITM (interferon-induced transmembrane) family are unique because they prevent infection before a virus can traverse the lipid bilayer of the cell. At least three human IFITM proteins-IFITM1, IFITM2, and IFITM3-have antiviral activities. These activities limit infection in cultured cells by many viruses, including dengue virus, Ebola virus, influenza A virus, severe acute respiratory syndrome coronavirus, and West Nile virus. Murine Ifitm3 controls influenza A virus infection in vivo, and polymorphisms in human correlate with the severity of both seasonal and highly pathogenic avian influenza virus. Here we review the discovery and characterization of the IFITM proteins, describe the spectrum of their antiviral activities, and discuss potential mechanisms underlying these effects.

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References

Huang I, Bosch B, Li F, Li W, Lee K, Ghiran S . SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. J Biol Chem. 2005; 281(6):3198-203. PMC: 8010168. DOI: 10.1074/jbc.M508381200. View

Xu Y, Yang G, Hu G . Binding of IFITM1 enhances the inhibiting effect of caveolin-1 on ERK activation. Acta Biochim Biophys Sin (Shanghai). 2009; 41(6):488-94. DOI: 10.1093/abbs/gmp034. View

Chandran K, Sullivan N, Felbor U, Whelan S, Cunningham J . Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science. 2005; 308(5728):1643-5. PMC: 4797943. DOI: 10.1126/science.1110656. View

Feeley E, Sims J, John S, Chin C, Pertel T, Chen L . IFITM3 inhibits influenza A virus infection by preventing cytosolic entry. PLoS Pathog. 2011; 7(10):e1002337. PMC: 3203188. DOI: 10.1371/journal.ppat.1002337. View

Jia R, Xu F, Qian J, Yao Y, Miao C, Zheng Y . Identification of an endocytic signal essential for the antiviral action of IFITM3. Cell Microbiol. 2014; 16(7):1080-93. PMC: 4065222. DOI: 10.1111/cmi.12262. View

Chen Y, Welte K, Gebhard D, Evans R . Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen. J Immunol. 1984; 133(5):2496-501. View

Smith S, Gibson M, Wash R, Ferrara F, Wright E, Temperton N . Chicken interferon-inducible transmembrane protein 3 restricts influenza viruses and lyssaviruses in vitro. J Virol. 2013; 87(23):12957-66. PMC: 3838109. DOI: 10.1128/JVI.01443-13. View

Bieniasz P . Intrinsic immunity: a front-line defense against viral attack. Nat Immunol. 2004; 5(11):1109-15. DOI: 10.1038/ni1125. View

Chandran K, Farsetta D, Nibert M . Strategy for nonenveloped virus entry: a hydrophobic conformer of the reovirus membrane penetration protein micro 1 mediates membrane disruption. J Virol. 2002; 76(19):9920-33. PMC: 136509. DOI: 10.1128/jvi.76.19.9920-9933.2002. View

10.

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. 1990; 145(7):2207-13. View

11.

Lange U, Adams D, Lee C, Barton S, Schneider R, Bradley A . Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster. Mol Cell Biol. 2008; 28(15):4688-96. PMC: 2493357. DOI: 10.1128/MCB.00272-08. View

12.

Chandran K, Nibert M . Protease cleavage of reovirus capsid protein mu1/mu1C is blocked by alkyl sulfate detergents, yielding a new type of infectious subvirion particle. J Virol. 1998; 72(1):467-75. PMC: 109396. DOI: 10.1128/JVI.72.1.467-475.1998. View

13.

Semler O, Garbes L, Keupp K, Swan D, Zimmermann K, Becker J . A mutation in the 5'-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet. 2012; 91(2):349-57. PMC: 3415541. DOI: 10.1016/j.ajhg.2012.06.011. View

14.

Mudhasani R, Tran J, Retterer C, Radoshitzky S, Kota K, Altamura L . IFITM-2 and IFITM-3 but not IFITM-1 restrict Rift Valley fever virus. J Virol. 2013; 87(15):8451-64. PMC: 3719792. DOI: 10.1128/JVI.03382-12. View

15.

John S, Chin C, Perreira J, Feeley E, Aker A, Savidis G . The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza A virus and dengue virus replication. J Virol. 2013; 87(14):7837-52. PMC: 3700195. DOI: 10.1128/JVI.00481-13. View

16.

Lange U, Saitou M, Western P, Barton S, Surani M . The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol. 2003; 3:1. PMC: 153542. DOI: 10.1186/1471-213x-3-1. View

17.

van der Schaar H, Rust M, Chen C, van der Ende-Metselaar H, Wilschut J, Zhuang X . Dissecting the cell entry pathway of dengue virus by single-particle tracking in living cells. PLoS Pathog. 2008; 4(12):e1000244. PMC: 2592694. DOI: 10.1371/journal.ppat.1000244. View

18.

Zhang Z, Liu J, Li M, Yang H, Zhang C . Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One. 2012; 7(11):e49265. PMC: 3499546. DOI: 10.1371/journal.pone.0049265. View

19.

Yount J, Moltedo B, Yang Y, Charron G, Moran T, Lopez C . Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3. Nat Chem Biol. 2010; 6(8):610-4. PMC: 2928251. DOI: 10.1038/nchembio.405. View

20.

Reid L, Brasnett A, GILBERT C, Porter A, Gewert D, Stark G . A single DNA response element can confer inducibility by both alpha- and gamma-interferons. Proc Natl Acad Sci U S A. 1989; 86(3):840-4. PMC: 286573. DOI: 10.1073/pnas.86.3.840. View