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Fam49/CYRI interacts with Rac1 and locally suppresses protrusions.

Loic Fort1,2, José Miguel Batista1,2, Peter A Thomason1

  • 1CRUK Beatson Institute, Glasgow, UK.

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Summary
This summary is machine-generated.

Scientists discovered CYRI (CYFIP-related Rac interactor), a protein that acts as a local inhibitor to control cell protrusion size and dynamics. This finding impacts understanding of cell migration and polarization.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biophysics

Background:

  • Actin-based cell protrusions are crucial for cell functions like migration and polarization.
  • Positive feedback mechanisms reinforce these protrusions, but regulators limiting their size and dynamics remain largely unknown.
  • Mathematical models predict local inhibitors of actin polymerization, but cellular counterparts were unidentified.

Purpose of the Study:

  • To identify and characterize novel regulators of actin-based cell protrusions.
  • To elucidate the molecular mechanism by which protrusion size and dynamics are controlled.
  • To investigate the role of identified regulators in cell migration and polarization.

Main Methods:

  • Depletion and overexpression of CYRI (CYFIP-related Rac interactor) in cultured cells.
  • Analysis of cell morphology, lamellipodia dynamics, and pseudopod formation using live imaging.
  • Optogenetic activation of Rac1 to induce pseudopods.
  • Biochemical assays to determine protein-protein interactions and localization.
  • Quantitative analysis of actin polymerization dynamics and Scar/WAVE complex recruitment.

Main Results:

  • CYRI (CYFIP-related Rac interactor) was identified as an evolutionarily conserved regulator of actin protrusions.
  • CYRI binds activated Rac1 via the DUF1394 domain, defining it as a Rac1-binding module.
  • CYRI depletion leads to broader lamellipodia and larger, longer-lived pseudopods upon Rac1 activation.
  • CYRI overexpression inhibits Scar/WAVE recruitment and actin polymerization, resulting in shorter protrusions.
  • CYRI functions as a local inhibitor, controlling protrusion polarity and plasticity.

Conclusions:

  • CYRI acts as a critical local inhibitor, balancing positive feedback signals to regulate actin-based protrusion size and dynamics.
  • The discovery of CYRI provides a cellular basis for previously theoretical models of protrusion regulation.
  • CYRI plays a key role in fundamental cellular processes including chemotaxis, cell migration, and epithelial polarization.