RASSF1A is required for the maintenance of nuclear actin levels

EMBO J. 2019 Aug 15;38(16):e101168. doi: 10.15252/embj.2018101168. Epub 2019 Jun 7.

Abstract

Nuclear actin participates in many essential cellular processes including gene transcription, chromatin remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin-9 and exportin-6, but how this transport is regulated remains unclear. Here, we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin-6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumour suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localises to the nuclear envelope (NE) and is required for nucleocytoplasmic actin transport and the concomitant regulation of myocardin-related transcription factor A (MRTF-A), a co-activator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MRTF-A/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MRTF-A/SRF in tumour suppression.

Keywords: MRTF-A; RASSF1A; exportin-6; nuclear actin; nuclear envelope.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Biological Transport
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cytoplasm / metabolism
  • DNA Methylation
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Karyopherins / metabolism
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Nuclear Envelope / metabolism*
  • Prognosis
  • Serum Response Factor / genetics*
  • Serum Response Factor / metabolism
  • Trans-Activators / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Actins
  • Karyopherins
  • MRTFA protein, human
  • RASSF1 protein, human
  • SRF protein, human
  • Serum Response Factor
  • Trans-Activators
  • Tumor Suppressor Proteins
  • XPO6 protein, human