Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCF Fbw7

Hyun Jin Kwun, Masahiro Shuda, Huichen Feng, Carlos J. Camacho, Patrick S. Moore, Yuan Chang

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Merkel cell polyomavirus (MCV) causes an aggressive human skin cancer, Merkel cell carcinoma, through expression of small T (sT) and large T (LT) viral oncoproteins. MCV sT is also required for efficient MCV DNA replication by the multifunctional MCV LT helicase protein. We find that LT is targeted for proteasomal degradation by the cellular SCFFbw7 E3 ligase, which can be inhibited by sT through its LT-stabilization domain (LSD). Consequently, sT also stabilizes cellular SCFFbw7 targets, including the cell-cycle regulators c-Myc and cyclin E. Mutating the sT LSD decreases LT protein levels and eliminates synergism in MCV DNA replication as well as sT-induced cell transformation. SCFFbw7 knockdown mimics sT-mediated stabilization of LT, but this knockdown is insufficient to fully reconstitute the transforming activity of a mutant LSD sT protein. Thus, MCV has evolved a regulatory system involving SCFFbw7 that controls viral replication but also contributes to host cell transformation.

Original languageEnglish (US)
Pages (from-to)125-135
Number of pages11
JournalCell Host and Microbe
Volume14
Issue number2
DOIs
StatePublished - Aug 14 2013

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

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