WASP and SCAR are evolutionarily conserved in actin-filled pseudopod-based motility

Abstract

Diverse eukaryotic cells crawl through complex environments using distinct modes of migration. To understand the underlying mechanisms and their evolutionary relationships, we must define each mode, and identify its phenotypic and molecular markers. Here, we focus on a widely dispersed migration mode characterized by dynamic, actin-filled pseudopods that we call “α-motility.” Mining genomic data reveals a clear trend: only organisms with both WASP and SCAR/WAVE—activators of branched actin assembly—make actin-filled pseudopods. While SCAR has been shown to drive pseudopod formation, WASP’s role in this process is controversial. We hypothesize that these genes together represent a genetic signature of α-motility, because both are used for pseudopod formation. WASP depletion from human neutrophils confirms that both proteins are involved in explosive actin polymerization, pseudopod formation, and cell migration, and colocalize to dynamic signaling structures. Moreover, retention of WASP together with SCAR correctly predicts α-motility in disease-causing chytrid fungi, which we show crawl at >30 μm/min with actin-filled pseudopods. By focusing on one migration mode in many eukaryotes, we identify a genetic marker of pseudopod formation, the morphological feature of α-motility, providing evidence for a widely distributed mode of cell crawling with a single evolutionary origin.

Cytoskeletal regulation of dendritic cells: An intricate balance between migration and presentation for tumor therapy

“…4). 124‐130 Combined usage of both WASp and WAVE/SCAR to assemble a branched network of actin filaments in pseudopods and lamellipodia allow immune cells to generate force to push the membrane forward and rapidly speed up migration 127,128 …”

“…In fact, large quantity of actin polymerization is needed for rapid lamellipodia and pseudopod formation during migration of immune cells 87,150 and lead to increased membrane tension 151 . This counteract efficient clathrin‐ and actin‐mediated endocytosis 127,151 . If pseudopod formation is inhibited by depletion of WASp, endocytosis is enhanced 127 .…”

“…[124][125][126][127][128][129][130] Combined usage of both WASp and WAVE/SCAR to assemble a branched network of actin filaments in pseudopods and lamellipodia allow immune cells to generate force to push the membrane forward and rapidly speed up migration. 127,128 Podosomes are important structures that are present in all monocyte-derived cells and participate in tissue invasion and matrix remodeling. [131][132][133] Formation of lamellipodia and podosomes at the leading edge allows DCs to make new contact sites when moving forward and retract the cell body.…”

“…151 This counteract efficient clathrin-and actin-mediated endocytosis. 127,151 If pseudopod formation is inhibited by depletion of WASp, endocytosis is enhanced. 127 It is interesting to note that the scaffolding protein Caveolin-1 (CAV1), implicated in both clathrin-mediated endocytosis and migration promotes the activation of Rac1 and membrane protrusions that favor DC chemotactic migration to the lymph nodes and activation of cytotoxic T cells.…”

“…127,151 If pseudopod formation is inhibited by depletion of WASp, endocytosis is enhanced. 127 It is interesting to note that the scaffolding protein Caveolin-1 (CAV1), implicated in both clathrin-mediated endocytosis and migration promotes the activation of Rac1 and membrane protrusions that favor DC chemotactic migration to the lymph nodes and activation of cytotoxic T cells. 152 Together, this suggests that the process of balanced migration and antigen uptake is spatio-temporally regulated.…”