Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores

Alberto Elosegui-Artola, Ion Andreu, Amy E.M. Beedle, Ainhoa Lezamiz, Marina Uroz, Anita J. Kosmalska, Roger Oria, Jenny Z. Kechagia, Palma Rico-Lastres, Anabel-Lise Le Roux, Catherine M. Shanahan, Xavier Trepat, Daniel Navajas, Sergi Garcia-Manyes, Pere Roca-Cusachs

Research output: Contribution to journalArticlepeer-review

835 Citations (Scopus)
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Abstract

YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.
Original languageEnglish
Pages (from-to)1397-1410.e14
JournalCell
Volume171
Issue number6
Early online date26 Oct 2017
DOIs
Publication statusPublished - 30 Nov 2017

Keywords

  • mechanotransduction
  • mechanosensing
  • transcription regulation
  • rigidity sensing
  • molecular mechanical stability
  • nuclear pores
  • nuclear transport
  • Hippo pathway
  • nuclear mechanics
  • atomic force microscopy

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