%0 Generic
%A Sitarska, Ewa
%C Heidelberg
%D 2022
%F heidok:30149
%R 10.11588/heidok.00030149
%T Deciphering the role of curvature-sensitive BAR domain proteins for cell migration
%U https://archiv.ub.uni-heidelberg.de/volltextserver/30149/
%X Cell motility has a critical role in a range of biological processes including development, immunity and disease. Navigation through complex and ever-changing environments often relies on the activity of actin-rich protrusions at the leading edge, also referred to as lamellipodia. Lamellipodia are known to exhibit areas of continuously rearranging membrane curvature, and their dynamics determines motion persistence. One group of proteins interesting in the context of membrane curvature are BAR domain proteins. However, whether and how these curvature-sensitive proteins contribute to leading edge dynamics and function, remains poorly understood. Here, we use neutrophils as a vertebrate model system of a highly migratory cell type. By combining RNAseq with a localization screen we identify two BAR proteins that are relevant for cell surface organization during migration: SH3BP1 and Snx33.     First, using fluorescent imaging and Atomic Force Microscopy, we show that SH3BP1 responds to changes in membrane mechanics and, vice-versa, modulates membrane tension. Using microfluidics, we further demonstrate that SH3BP1 is important for cell navigation through complex environments. Namely, its knockout displays increased cell speed and decision making during directed cell migration.    Next, we used the above techniques complemented with machine learning-based segmentation for time-resolved TIRF microscopy to understand the role of Snx33. We show that motion persistence and directionality, in both freely moving and environmentally constrained cells, depends on Snx33 activity. Specifically, Snx33 has an inhibitory effect on the lamellipodia dynamics by regulating WAVE2-driven actin polymerization. Our work exposes a novel mechanism by which cells steer protrusions upon encountering obstacles that facilitates efficient migration. In summary, we discovered novel functions of the curvature-sensitive proteins SH3BP1 and Snx33 in regulating cell surface mechanics and efficiency of directed cell migration.