Adaptor complex-mediated trafficking of Newcastle disease virus fusion protein is regulated by the YLMY motif of its cytoplasmic tail

ABSTRACT

Previously, we reported that the mediation of Newcastle disease virus (NDV) pathogenicity by the ⁵²⁴YLMY⁵²⁷ motif depends mainly on the regulation of F protein transport to the cell surface. The virus and host determinants that govern this intracellular trafficking remain unknown. Here, we confirmed that host adaptor protein (AP) complexes are involved in NDV infection using small interfering RNA. The transport of viral F protein to the cell surface depends on host transport proteins. We observed that the trends for host expression of AP complexes AP1M1 and AP2M1 were similar to those of mutated F proteins, especially in the membrane protein. NDV F protein interacted with AP1M1 and AP2M1, and the YLMY motif influenced this interaction. Knockdown of AP1M1 or AP2M1 suppressed the intracellular and extracellular virus titre of mutated-YLMY-motif NDVs, especially rSG10*-F/Y527A and rSG10*-F/Y524AY527A, to varying degrees. Therefore, the YLMY motif regulates AP-mediated viral F protein transportation from the cytoplasm to the cell surface and subsequently affects viral titer. We further found that the YLMY-motif mutants were differently associated with the process of AAK1 and GAK kinase-mediated AP – viral F protein interaction. These data demonstrate that the essential YLMY motif located in the NDV F protein cytoplasmic tail recruits AP to direct the F protein to the cell surface, which is necessary for its ability to affect virus budding. This study provides support for a deeper understanding of virus and host determinants that facilitate virus trafficking, which can be exploited in the design of novel antiviral therapies.

KEYWORDS:

• Newcastle disease virus, NDV
• F protein
• cytoplasmic tail
• YLMY motif
• AP transport

Acknowledgments

This work was supported by the 2115 Talent Development Program of China Agricultural University. We thank Katie Oakley, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.

Author contribution statement

Conceptualization: Y.B., Y.Z., and G.Z.; methodology: Y.B., Q.T., D.F., R.L., H.W., W.J., and X.Z.; investigation: Y.B., Q.T., and X.L.; writing – original draft: Y.B. and J.X.; writing – review & editing: Y.B., Y.Z., and G.Z.; supervision: J.X. and G.Z.; project administration: G. Z.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21505594.2022.2136433.

Additional information

Funding

The work was supported by the the 2115 Talent Development Program of China Agricultural University .