Article

Actin binding to WH2 domains regulates nuclear import of the multifunctional actin regulator JMY

Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Molecular biology of the cell (Impact Factor: 5.98). 03/2012; 23(5):853-63. DOI: 10.1091/mbc.E11-12-0992
Source: PubMed

ABSTRACT Junction-mediating and regulatory protein (JMY) is a regulator of both transcription and actin filament assembly. In response to DNA damage, JMY accumulates in the nucleus and promotes p53-dependent apoptosis. JMY's actin-regulatory activity relies on a cluster of three actin-binding Wiskott-Aldrich syndrome protein homology 2 (WH2) domains that nucleate filaments directly and also promote nucleation activity of the Arp2/3 complex. In addition to these activities, we find that the WH2 cluster overlaps an atypical, bipartite nuclear localization sequence (NLS) and controls JMY's subcellular localization. Actin monomers bound to the WH2 domains block binding of importins to the NLS and prevent nuclear import of JMY. Mutations that impair actin binding, or cellular perturbations that induce actin filament assembly and decrease the concentration of monomeric actin in the cytoplasm, cause JMY to accumulate in the nucleus. DNA damage induces both cytoplasmic actin polymerization and nuclear import of JMY, and we find that damage-induced nuclear localization of JMY requires both the WH2/NLS region and importin β. On the basis of our results, we propose that actin assembly regulates nuclear import of JMY in response to DNA damage.

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    • "TABLE I. Continued Proteins IDR(s) Functions related to the IDR(s) Role of disorder Refs JMY, MRTF-A or Phactr1 transcriptional cofactors repeats of WH2/ßT or of RPEL-motifs G-actin and importin-a binding , G-actin-concentrationsensing mechanism regulating nuclear localization for transcription signal integrator, mutually exclusive interactions, cooperative G-actin binding [Mouilleron et al., 2012; Zuchero et al., 2012] "
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