m6A Reader YTHDC1 Impairs Respiratory Syncytial Virus Infection by Downregulating Membrane CX3CR1 Expression
Lucas W. Picavet (University Medical Center Utrecht)
Ellen C.N. van Vroonhoven (University Medical Center Utrecht)
Rianne C. Scholman (University Medical Center Utrecht)
Yesper T.H. Smits (University Medical Center Utrecht)
Rupa Banerjee (University Medical Center Utrecht, The Oncode Institute)
Sjanna B. Besteman (University Medical Center Utrecht)
Mattheus C. Viveen (University Medical Center Utrecht)
Michiel M. van der Vlist (The Oncode Institute, University Medical Center Utrecht)
Marvin E. Tanenbaum (The Oncode Institute, TU Delft - BN/Marvin Tanenbaum Lab, University Medical Center Utrecht)
Robert J. Lebbink (University Medical Center Utrecht)
Sebastiaan J. Vastert (University Medical Center Utrecht)
Jorg van Loosdregt (University Medical Center Utrecht)
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Abstract
Respiratory syncytial virus (RSV) is the most prevalent cause of acute lower respiratory infection in young children. Currently, the first RSV vaccines are approved by the FDA. Recently, N6-methyladenosine (m6A) RNA methylation has been implicated in the regulation of the viral life cycle and replication of many viruses, including RSV. m6A methylation of RSV RNA has been demonstrated to promote replication and prevent anti-viral immune responses by the host. Whether m6A is also involved in viral entry and whether m6A can also affect RSV infection via different mechanisms than methylation of viral RNA is poorly understood. Here, we identify m6A reader YTH domain-containing protein 1 (YTHDC1) as a novel negative regulator of RSV infection. We demonstrate that YTHDC1 abrogates RSV infection by reducing the expression of RSV entry receptor CX3C motif chemokine receptor 1 (CX3CR1) on the cell surface of lung epithelial cells. Altogether, these data reveal a novel role for m6A methylation and YTHDC1 in the viral entry of RSV. These findings may contribute to the development of novel treatment options to control RSV infection.
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