Fam49/CYRI interacts with Rac1 and locally suppresses protrusions

Fort, Loic and Batista, José Miguel and Thomason, Peter A. and Spence, Heather J. and Whitelaw, Jamie A. and Tweedy, Luke and Greaves, Jennifer and Martin, Kirsty J. and Anderson, Kurt I. and Brown, Peter and Lilla, Sergio and Neilson, Matthew P. and Tafelmeyer, Petra and Zanivan, Sara and Ismail, Shehab and Bryant, David M. and Tomkinson, Nicholas C. O. and Chamberlain, Luke H. and Mastick, Grant S. and Insall, Robert H. and Machesky, Laura M. (2018) Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nature Cell Biology, 20. pp. 1159-1171.

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    Abstract

    Actin-based protrusions are reinforced through positive feedback, but it is unclear what restricts their size, or limits positive signals when they retract or split. We identify an evolutionarily conserved regulator of actin-based protrusion: CYRI (CYFIP-related Rac interactor) also known as Fam49 (family of unknown function 49). CYRI binds activated Rac1 via a domain of unknown function (DUF1394) shared with CYFIP, defining DUF1394 as a Rac1-binding module. CYRI-depleted cells have broad lamellipodia enriched in Scar/WAVE, but reduced protrusion–retraction dynamics. Pseudopods induced by optogenetic Rac1 activation in CYRI-depleted cells are larger and longer lived. Conversely, CYRI overexpression suppresses recruitment of active Scar/WAVE to the cell edge, resulting in short-lived, unproductive protrusions. CYRI thus focuses protrusion signals and regulates pseudopod complexity by inhibiting Scar/WAVE-induced actin polymerization. It thus behaves like a ‘local inhibitor’ as predicted in widely accepted mathematical models, but not previously identified in cells. CYRI therefore regulates chemotaxis, cell migration and epithelial polarization by controlling the polarity and plasticity of protrusions.