Journal
JOURNAL OF VIROLOGY
Volume 86, Issue 22, Pages 12148-12160Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01133-12
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Funding
- Public Health Service [AI-73697, AI-85062]
- National Institute of Allergy and Infectious Diseases [T32 AI-7611]
- National Cancer Institute [T32 CA-9682]
- Vanderbilt Ingram Cancer Center (NIH) [P30 CA-68485]
- Vanderbilt Digestive Disease Research Center (NIH) [DK-58404]
- Vanderbilt CTSA from the NCRR/NIH [UL1 RR-24975-01]
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Paramyxoviruses use a specialized fusion protein to merge the viral envelope with cell membranes and initiate infection. Most paramyxoviruses require the interaction of two viral proteins to enter cells; an attachment protein binds cell surface receptors, leading to the activation of a fusion (F) protein that fuses the viral envelope and host cell plasma membrane. In contrast, human metapneumovirus (HMPV) expressing only the F protein is replication competent, suggesting a primary role for HMPV F in attachment and fusion. We previously identified an invariant arginine-glycine-aspartate (RGD) motif in the HMPV F protein and showed that the RGD-binding integrin alpha V beta 1-promoted HMPV infection. Here we show that both HMPV F-mediated binding and virus entry depend upon multiple RGD-binding integrins and that HMPV F can mediate binding and fusion in the absence of the viral attachment (G) protein. The invariant F-RGD motif is critical for infection, as an F-RAE virus was profoundly impaired. Further, F-integrin binding is required for productive viral RNA transcription, indicating that RGD-binding integrins serve as receptors for the HMPV fusion protein. Thus, HMPV F is triggered to induce virus-cell fusion by interactions with cellular receptors in a manner that is independent of the viral G protein. These results suggest a stepwise mechanism of HMPV entry mediated by the F protein through its interactions with cellular receptors, including RGD-binding integrins.
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