The Interferon-induced Transmembrane Proteins, IFITM1, IFITM2, and IFITM3 Inhibit Hepatitis C Virus Entry.
The interferon-induced transmembrane (IFITM) family of proteins have recently been identified as important host effector molecules of the type I interferon response against viruses. IFITM1 has been identified as a potent antiviral effector against hepatitis C virus (HCV), whereas the related family members IFITM2 and IFITM3 have been described to have antiviral effects against a broad range of RNA viruses. Here, we demonstrate that IFITM2 and IFITM3 play an integral role in the interferon response against HCV and act at the level of late entry stages of HCV infection. We have established that in hepatocytes, IFITM2 and IFITM3 localize to the late and early endosomes, respectively, as well as the lysosome. Furthermore, we have demonstrated that S-palmitoylation of all three IFITM proteins is essential for anti-HCV activity, whereas the conserved tyrosine residue in the N-terminal domain of IFITM2 and IFITM3 plays a significant role in protein localization. However, this tyrosine was found to be dispensable for anti-HCV activity, with mutation of the tyrosine resulting in an IFITM1-like phenotype with the retention of anti-HCV activity and co-localization of IFITM2 and IFITM3 with CD81. In conclusion, we propose that the IFITM proteins act in a coordinated manner to restrict HCV infection by targeting the endocytosed HCV virion for lysosomal degradation and demonstrate that the actions of the IFITM proteins are indeed virus and cell-type specific.
From the School of Biological Sciences, and the Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia 5005, Australia, the Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, 5000, Australia, and.
Sumudu K
SK
Narayana
From the School of Biological Sciences, and the Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia 5005, Australia, the Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, 5000, Australia, and.
Karla J
KJ
Helbig
From the School of Biological Sciences, and the Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia 5005, Australia, the Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, 5000, Australia, and.
Erin M
EM
McCartney
From the School of Biological Sciences, and the Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia 5005, Australia, the Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, 5000, Australia, and.
Nicholas S
NS
Eyre
the Inflammation and Infection Research Centre, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
Rowena A
RA
Bull
the Inflammation and Infection Research Centre, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
Auda
A
Eltahla
the Inflammation and Infection Research Centre, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
Andrew R
AR
Lloyd
From the School of Biological Sciences, and the Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia 5005, Australia, the Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, 5000, Australia, and michael.beard@adelaide.edu.au.
Michael R
MR
Beard
D000943:Antigens, Differentiation / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000503:physiopathology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D054878:Lipoylation; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*
D000943:Antigens, Differentiation; C080081:IFITM2 protein, human; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C062010:leu-13 antigen
cellular immune response; hepatitis C virus (HCV); interferon; interferon-induced transmembrane (IFITM) proteins; protein palmitoylation; protein phosphorylation