Cyclin D3 restricts SARS‐CoV‐2 envelope incorporation into virions and interferes with viral spread.

The COVID‐19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) presents a great threat to human health. The interplay between the virus and host plays a crucial role in successful virus replication and transmission. Understanding host–virus interactions are essential for the development of new COVID‐19 treatment strategies. Here, we show that SARS‐CoV‐2 infection triggers redistribution of cyclin D1 and cyclin D3 from the nucleus to the cytoplasm, followed by proteasomal degradation. No changes to other cyclins or cyclin‐dependent kinases were observed. Further, cyclin D depletion was independent of SARS‐CoV‐2‐mediated cell cycle arrest in the early S phase or S/G2/M phase. Cyclin D3 knockdown by small‐interfering RNA specifically enhanced progeny virus titres in supernatants. Finally, cyclin D3 co‐immunoprecipitated with SARS‐CoV‐2 envelope (E) and membrane (M) proteins. We propose that cyclin D3 impairs the efficient incorporation of envelope protein into virions during assembly and is depleted during SARS‐CoV‐2 infection to restore efficient assembly and release of newly produced virions. Synopsis: Many viruses, including coronaviruses, manipulate cell cycle progression through cyclin‐CDKs complexes. Surprisingly, cyclin D3 degradation induced by SARS‐CoV‐2 promotes infection not via cell cycle arrest but by relieving cyclin interference with virion assembly. Productive SARS‐CoV‐2 infection induces cell cycle arrest and depletes cyclin D from infected cells.Cell cycle arrest induced by SARS‐CoV‐2 is not dependent on cyclin D degradation.Cyclin D3 knockdown enhances SARS‐CoV‐2 infection.Cyclin D3 associates with envelope (E) and membrane (M) proteins of SARS‐CoV‐2 and impairs efficient envelope protein incorporation into virions.Efficient assembly and release of newly produced SARS‐CoV‐2 virions depends on virus‐induced redistribution and degradation of host cell D‐type cyclins. [ABSTRACT FROM AUTHOR]