Monoubiquitination of filamin B regulates vascular endothelial growth factor-mediated trafficking of histone deacetylase 7

Yu Ting Su, Chengzhuo Gao, Yu Liu, Shuang Guo, Anthony Wang, Benlian Wang, Hediye Erdjument-Bromage, Masaru Miyagi, Paul Tempst, Hung Ying Kao

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Nucleocytoplasmic shuttling of class IIa of histone deacetylases (HDACs) is a key mechanism that controls cell fate and animal development. We have identified the filamin B (FLNB) as a novel HDAC7-interacting protein that is required for temporal and spatial regulation of vascular endothelial growth factor (VEGF)-mediated HDAC7 cytoplasmic sequestration. This interaction occurs in the cytoplasm and requires monoubiquitination of an evolutionarily conserved lysine 1147 (K1147) in the immunoglobulin (Ig)-like repeat 10 (R10) of FLNB and the nuclear localization sequence of HDAC7. Inhibition of protein kinase C (PKC) blocks VEGF-induced ubiquitination of FLNB and its interaction with HDAC7. Small interfering RNA (siRNA) knockdown of FLNB or ubiquitin (Ub) in human primary endothelial cells blocks VEGF-mediated cytoplasmic accumulation of HDAC7, reduces VEGF-induced expression of the HDAC7 target genes Mmp-10 and Nur77, and inhibits VEGF-induced vascular permeability. Using dominant negative mutants and rescue ex periments, we demonstrate the functional significance of FLNB K1147 to interfere with the ability of phorbol myristate acetate (PMA) to promote FLNB-mediated cytoplasmic accumulation of HDAC7. Taken together, our data show that VEGF and PKC promote degradation-independent protein ubiquitination of FLNB to control intracellular trafficking of HDAC7.

Original languageEnglish
Pages (from-to)1546-1560
Number of pages15
JournalMolecular and Cellular Biology
Volume33
Issue number8
DOIs
Publication statusPublished - 2013 Apr

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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