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

doi:10.1016/j.chom.2013.06.008

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 journal › Article › peer-review

142 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 SCF^Fbw7 E3 ligase, which can be inhibited by sT through its LT-stabilization domain (LSD). Consequently, sT also stabilizes cellular SCF^Fbw7 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. SCF^Fbw7 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 SCF^Fbw7 that controls viral replication but also contributes to host cell transformation.

Original language	English (US)
Pages (from-to)	125-135
Number of pages	11
Journal	Cell Host and Microbe
Volume	14
Issue number	2
DOIs	https://doi.org/10.1016/j.chom.2013.06.008
State	Published - Aug 14 2013

All Science Journal Classification (ASJC) codes

Parasitology
Microbiology
Virology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.chom.2013.06.008

Cite this

@article{02f457fb41854f9d85e27a91c9bc548a,

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

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.",

author = "Kwun, {Hyun Jin} and Masahiro Shuda and Huichen Feng and Camacho, {Carlos J.} and Moore, {Patrick S.} and Yuan Chang",

note = "Funding Information: We thank Bert Vogelstein for providing the HCT116 cell lines, Keiichi I. Nakayama for the HA-Fbw7 and Flag-c-Myc plasmids, and Robert Weinberg for providing the SV40 plasmid. We thank Missy Mazzoli for help with the manuscript. This study was funded by the National Institutes of Health grants CA136363 and CA120726 to P.S.M. and Y.C., who are also supported as American Cancer Society Research Professors. M.S. was supported in part by the University of Pittsburgh Skin Cancer SPORE CA12197305. H.F. is a Lymphoma Research Foundation Fellow (LRF124915). C.J.C. was supported by NIH GM097082-01. UPCI-shared resources used in this study are supported by P30CA047904. ",

year = "2013",

month = aug,

day = "14",

doi = "10.1016/j.chom.2013.06.008",

language = "English (US)",

volume = "14",

pages = "125--135",

journal = "Cell Host and Microbe",

issn = "1931-3128",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCF Fbw7

AU - Kwun, Hyun Jin

AU - Shuda, Masahiro

AU - Feng, Huichen

AU - Camacho, Carlos J.

AU - Moore, Patrick S.

AU - Chang, Yuan

N1 - Funding Information: We thank Bert Vogelstein for providing the HCT116 cell lines, Keiichi I. Nakayama for the HA-Fbw7 and Flag-c-Myc plasmids, and Robert Weinberg for providing the SV40 plasmid. We thank Missy Mazzoli for help with the manuscript. This study was funded by the National Institutes of Health grants CA136363 and CA120726 to P.S.M. and Y.C., who are also supported as American Cancer Society Research Professors. M.S. was supported in part by the University of Pittsburgh Skin Cancer SPORE CA12197305. H.F. is a Lymphoma Research Foundation Fellow (LRF124915). C.J.C. was supported by NIH GM097082-01. UPCI-shared resources used in this study are supported by P30CA047904.

PY - 2013/8/14

Y1 - 2013/8/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84882318903&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84882318903&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2013.06.008

DO - 10.1016/j.chom.2013.06.008

M3 - Article

C2 - 23954152

AN - SCOPUS:84882318903

SN - 1931-3128

VL - 14

SP - 125

EP - 135

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 2

ER -