Actin Filaments Couple the Protrusive Tips to the Nucleus through the I-BAR Domain Protein IRSp53 during the Migration of Cells on 1D Fibers.

Abstract

The cell migration cycle, well-established in2D, proceeds with forming new protrusive structures at the cell membrane andsubsequentredistribution of contractile machinery. Three-dimensional (3D) environments are complexand composed of 1D fibers, and 1D fibers are shown to recapitulateessential features of 3D migration. However, the establishment of protrusiveactivity at the cell membrane and contractilityin1Dfibrous environmentsremains partially understood. Here the role of membrane curvatureregulator IRSp53 is examined as a coupler between actin filaments and plasmamembraneduring cell migration on single, suspended 1D fibers. IRSp53 depletion reducedcell-length spanning actin stress fibers that originate from thecellperiphery, protrusive activity, and contractility, leading touncoupling of the nucleus from cellular movements. A theoreticalmodel capable of predicting the observed transition of IRSp53-depleted cellsfrom rapid stick-slip migration to smooth and slower migration due toreducedactin polymerization at the cell edges is developed, which is verified by directmeasurements of retrograde actin flow using speckle microscopy. Overall, it isfound that IRSp53 mediates actin recruitment at the cellular tips leading tothe establishment of cell-length spanning fibers, thus demonstrating a uniquerole of IRSp53 in controlling cell migration in 3D.