STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap

Nat Commun. 2018 May 29;9(1):2124. doi: 10.1038/s41467-018-04404-4.

Abstract

The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Actin Capping Proteins / metabolism*
  • Acyltransferases
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Nonmuscle Myosin Type IIB / metabolism
  • Nuclear Envelope / metabolism*
  • Nuclear Proteins / metabolism
  • Transcription Factors / metabolism
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Actin Capping Proteins
  • Guanine Nucleotide Exchange Factors
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RAC1 protein, human
  • SYNE2 protein, human
  • TIAM2 protein, human
  • Transcription Factors
  • Acyltransferases
  • TAFAZZIN protein, human
  • Nonmuscle Myosin Type IIB
  • rac1 GTP-Binding Protein