SCF(Fbxw15) mediates histone acetyltransferase binding to origin recognition complex (HBO1) ubiquitin-proteasomal degradation to regulate cell proliferation

Histone acetyltransferase binding to origin recognition complex (HBO1) plays a crucial role in DNA replication licensing and cell proliferation, yet its molecular regulation in cells is relatively unknown. Here an uncharacterized protein, Fbxw15, directly interacts with HBO1, a labile protein (t½ =...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2013-03, Vol.288 (9), p.6306-6316
Main Authors: Zou, Chunbin, Chen, Yan, Smith, Rebecca M, Snavely, Courtney, Li, Jin, Coon, Tiffany A, Chen, Bill B, Zhao, Yutong, Mallampalli, Rama K
Format: Article
Language:English
Subjects:
Acetylation
Animals
Cell Line
Cell Proliferation
F-Box Proteins - genetics
F-Box Proteins - metabolism
Gene Silencing
Histone Acetyltransferases - genetics
Histone Acetyltransferases - metabolism
Histones - genetics
Histones - metabolism
Humans
MAP Kinase Kinase 1 - genetics
MAP Kinase Kinase 1 - metabolism
Mice
Proteasome Endopeptidase Complex - genetics
Proteasome Endopeptidase Complex - metabolism
Proteolysis
Ubiquitin - genetics
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Histone acetyltransferase binding to origin recognition complex (HBO1) plays a crucial role in DNA replication licensing and cell proliferation, yet its molecular regulation in cells is relatively unknown. Here an uncharacterized protein, Fbxw15, directly interacts with HBO1, a labile protein (t½ = ∼3 h), to mediate its ubiquitination (Lys(338)) and degradation in the cytoplasm. Fbxw15-mediated HBO1 depletion required mitogen-activated protein kinase 1 (Mek1), which was sufficient to trigger HBO1 phosphorylation and degradation in cells. Mek1 ability to produce HBO1 degradation was blocked by Fbxw15 silencing. Lipopolysaccharide induced HBO1 degradation, an effect abrogated by Fbxw15 or Mek1 cellular depletion. Modulation of Fbxw15 levels was able to differentially regulate histone H3K14 acetylation and cellular proliferation by altering HBO1 levels. These studies authenticate Fbxw15 as a ubiquitin E3 ligase subunit that mediates endotoxin-induced HBO1 depletion in cells, thereby controlling cell replicative capacity.
ISSN:1083-351X
DOI:10.1074/jbc.M112.426882