The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity.
The interferon-inducible transmembrane (IFITM) proteins inhibit a wide range of viruses. We previously reported the inhibition of human immunodeficiency virus type 1 (HIV-1) strain BH10 by human IFITM1, 2 and 3. It is unknown whether other HIV-1 strains are similarly inhibited by IFITMs and whether there exists viral countermeasure to overcome IFITM inhibition. We report here that the HIV-1 NL4-3 strain (HIV-1NL4-3) is not restricted by IFITM1 and its viral envelope glycoprotein is partly responsible for this insensitivity. However, HIV-1NL4-3 is profoundly inhibited by an IFITM1 mutant, known as Δ(117-125), which is deleted of 9 amino acids at the C-terminus. In contrast to the wild type IFITM1, which does not affect HIV-1 entry, the Δ(117-125) mutant diminishes HIV-1NL4-3 entry by 3-fold. This inhibition correlates with the predominant localization of Δ(117-125) to the plasma membrane where HIV-1 entry occurs. In spite of strong conservation of IFITM1 among most species, mouse IFITM1 is 19 amino acids shorter at its C-terminus as compared to human IFITM1 and, like the human IFITM1 mutant Δ(117-125), mouse IFITM1 also inhibits HIV-1 entry. This is the first report illustrating the role of viral envelope protein in overcoming IFITM1 restriction. The results also demonstrate the importance of the C-terminal region of IFITM1 in modulating the antiviral function through controlling protein subcellular localization.
Key Laboratory of Molecular Microbiology and Biotechnology (Ministry of Education) and Key Laboratory of Microbial Functional Genomics (Tianjin), College of Life Sciences, Nankai University, Tianjin, 300071, China; Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada.
Rui
R
Jia
Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada; Department of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada.
Shilei
S
Ding
Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada.
Qinghua
Q
Pan
Department of Molecular Microbiology & Immunology, School of Medicine, Bond Life Sciences Center, University of Missouri, Columbia, Missouri, 65211-7310, United States of America.
Shan-Lu
SL
Liu
Key Laboratory of Molecular Microbiology and Biotechnology (Ministry of Education) and Key Laboratory of Microbial Functional Genomics (Tianjin), College of Life Sciences, Nankai University, Tianjin, 300071, China.
Wentao
W
Qiao
Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, H3T 1E2, Canada; Department of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada.
Chen
C
Liang
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D013045:Species Specificity; D014759:Viral Envelope Proteins / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000943:Antigens, Differentiation; D014759:Viral Envelope Proteins; C062010:leu-13 antigen