WASP integrates substrate topology and cell polarity to guide neutrophil migration

Rachel M. Brunetti; Gabriele Kockelkoren; Preethi Raghavan; George R.R. Bell; Derek Britain; Natasha Puri; Sean R. Collins; Manuel D. Leonetti; Dimitrios Stamou; Orion D. Weiner

doi:10.1083/jcb.202104046

WASP integrates substrate topology and cell polarity to guide neutrophil migration

Rachel M. Brunetti, Gabriele Kockelkoren, Preethi Raghavan, George R.R. Bell, Derek Britain, Natasha Puri, Sean R. Collins, Manuel D. Leonetti, Dimitrios Stamou, Orion D. Weiner^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Journal article › Research › peer-review

23 Citations (Scopus)

24 Downloads (Pure)

Abstract

To control their movement, cells need to coordinate actin assembly with the geometric features of their substrate. Here, we uncover a role for the actin regulator WASP in the 3D migration of neutrophils. We show that WASP responds to substrate topology by enriching to sites of inward, substrate-induced membrane deformation. Superresolution imaging reveals that WASP preferentially enriches to the necks of these substrate-induced invaginations, a distribution that could support substrate pinching. WASP facilitates recruitment of the Arp2/3 complex to these sites, stimulating local actin assembly that couples substrate features with the cytoskeleton. Surprisingly, WASP only enriches to membrane deformations in the front half of the cell, within a permissive zone set by WASP’s front-biased regulator Cdc42. While WASP KO cells exhibit relatively normal migration on flat substrates, they are defective at topology-directed migration. Our data suggest that WASP integrates substrate topology with cell polarity by selectively polymerizing actin around substrate-induced membrane deformations in the front half of the cell.

Original language	English
Article number	e202104046
Journal	Journal of Cell Biology
Volume	221
Issue number	2
Number of pages	30
ISSN	0021-9525
DOIs	https://doi.org/10.1083/jcb.202104046
Publication status	Published - 7 Feb 2022

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grant F31 HL143882 (R.M. Brunetti), National Science Foundation Graduate Research Fellowships Program grant 1650042 (G.R.R. Bell), National Institutes of Health grant GM118167 (O.D. Weiner), National Science Foundation/Biotechnology and Biological Sciences Research Council grant 2019598 (O.D. Weiner), the National Science Foundation Center for Cellular Construction (DBI-1548297), and a Novo Nordisk Foundation grant for the Center for Geometrically Engineered Cellular Systems (NNF17OC0028176). The authors declare no competing financial interests.

Publisher Copyright:
© 2021 Brunetti et al.

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Cite this

WASP integrates substrate topology and cell polarity to guide neutrophil migration. / Brunetti, Rachel M.; Kockelkoren, Gabriele; Raghavan, Preethi; Bell, George R.R.; Britain, Derek; Puri, Natasha; Collins, Sean R.; Leonetti, Manuel D.; Stamou, Dimitrios; Weiner, Orion D.

In: Journal of Cell Biology, Vol. 221, No. 2, e202104046, 07.02.2022.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "WASP integrates substrate topology and cell polarity to guide neutrophil migration",

abstract = "To control their movement, cells need to coordinate actin assembly with the geometric features of their substrate. Here, we uncover a role for the actin regulator WASP in the 3D migration of neutrophils. We show that WASP responds to substrate topology by enriching to sites of inward, substrate-induced membrane deformation. Superresolution imaging reveals that WASP preferentially enriches to the necks of these substrate-induced invaginations, a distribution that could support substrate pinching. WASP facilitates recruitment of the Arp2/3 complex to these sites, stimulating local actin assembly that couples substrate features with the cytoskeleton. Surprisingly, WASP only enriches to membrane deformations in the front half of the cell, within a permissive zone set by WASP{\textquoteright}s front-biased regulator Cdc42. While WASP KO cells exhibit relatively normal migration on flat substrates, they are defective at topology-directed migration. Our data suggest that WASP integrates substrate topology with cell polarity by selectively polymerizing actin around substrate-induced membrane deformations in the front half of the cell.",

author = "Brunetti, {Rachel M.} and Gabriele Kockelkoren and Preethi Raghavan and Bell, {George R.R.} and Derek Britain and Natasha Puri and Collins, {Sean R.} and Leonetti, {Manuel D.} and Dimitrios Stamou and Weiner, {Orion D.}",

note = "Funding Information: This work was supported by National Institutes of Health grant F31 HL143882 (R.M. Brunetti), National Science Foundation Graduate Research Fellowships Program grant 1650042 (G.R.R. Bell), National Institutes of Health grant GM118167 (O.D. Weiner), National Science Foundation/Biotechnology and Biological Sciences Research Council grant 2019598 (O.D. Weiner), the National Science Foundation Center for Cellular Construction (DBI-1548297), and a Novo Nordisk Foundation grant for the Center for Geometrically Engineered Cellular Systems (NNF17OC0028176). The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2021 Brunetti et al.",

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AB - To control their movement, cells need to coordinate actin assembly with the geometric features of their substrate. Here, we uncover a role for the actin regulator WASP in the 3D migration of neutrophils. We show that WASP responds to substrate topology by enriching to sites of inward, substrate-induced membrane deformation. Superresolution imaging reveals that WASP preferentially enriches to the necks of these substrate-induced invaginations, a distribution that could support substrate pinching. WASP facilitates recruitment of the Arp2/3 complex to these sites, stimulating local actin assembly that couples substrate features with the cytoskeleton. Surprisingly, WASP only enriches to membrane deformations in the front half of the cell, within a permissive zone set by WASP’s front-biased regulator Cdc42. While WASP KO cells exhibit relatively normal migration on flat substrates, they are defective at topology-directed migration. Our data suggest that WASP integrates substrate topology with cell polarity by selectively polymerizing actin around substrate-induced membrane deformations in the front half of the cell.

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