The Nance-Horan syndrome protein NHS regulates cell migration persistence by organizing WAVE and N-WASP nucleation-promoting factor complexes
Abstract
The function of the NHS gene that is responsible for the Nance-Horan Syndrome has remained elusive at the cellular level. Using CRISPR/Cas9, we inactivated the NHS gene in MCF10A cells and characterized the isoforms expressed in these cells. NHS KO cells displayed reduced migration persistence, a phenotype that was fully rescued by the long isoform 1 (i1) that contains a N-terminal WAVE Homology Domain (WHD), but only partially rescued by the short isoform 2 (i2), which does not. Patient mutations resulting in NHS proteins truncated at their C-terminus also reduced the ability of NHS i1 to rescue migration persistence. Using Tandem Affinity Purification (TAP) of NHS i1 and mass spectrometry, we identified as major NHS partners, all subunits of the WAVE Regulatory Complex (WRC) except WAVE subunits themselves, indicating that the WHD of NHS assembles a WAVE Shell Complex (WSC). The Arp2/3 complex and the Nucleation Promoting Factor (NPF) WAVE that activates it are critical for migration persistence. To investigate the role of the NHS-containing WSC, we performed TAP of the ABI1 subunit in parental and NHS KO cells and identified differential partners associated with ABI1 only in parental cells, but not in NHS KO cells. The most abundant of these were the WIPF2/N-WASP complex, which together with the kinase ABL2, was also critical for migration persistence. These results suggest that NHS controls cell migration by remodeling NPF complexes and their higher order assembly.
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BibTeX
@article{tsydenzhapova2026nancehoran,
title = {{The Nance-Horan syndrome protein NHS regulates cell migration persistence by organizing WAVE and N-WASP nucleation-promoting factor complexes}},
author = {Ekaterina Tsydenzhapova and Artem Fokin and Nicolas David and Nathalie Rocques and Anna Polesskaya and Iman Haddad and Joëlle Vinh and Raphaël Guérois and Alexis Gautreau},
journal = {Journal of Biological Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.jbc.2026.113443},
url = {https://hal.science/hal-05733250v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - The Nance-Horan syndrome protein NHS regulates cell migration persistence by organizing WAVE and N-WASP nucleation-promoting factor complexes
AU - Ekaterina Tsydenzhapova
AU - Artem Fokin
AU - Nicolas David
AU - Nathalie Rocques
AU - Anna Polesskaya
AU - Iman Haddad
AU - Joëlle Vinh
AU - Raphaël Guérois
AU - Alexis Gautreau
PY - 2026
DA - 2026/09/01
JO - Journal of Biological Chemistry
DO - 10.1016/j.jbc.2026.113443
UR - https://hal.science/hal-05733250v1
AB - The function of the NHS gene that is responsible for the Nance-Horan Syndrome has remained elusive at the cellular level. Using CRISPR/Cas9, we inactivated the NHS gene in MCF10A cells and characterized the isoforms expressed in these cells. NHS KO cells displayed reduced migration persistence, a phenotype that was fully rescued by the long isoform 1 (i1) that contains a N-terminal WAVE Homology Domain (WHD), but only partially rescued by the short isoform 2 (i2), which does not. Patient mutations resulting in NHS proteins truncated at their C-terminus also reduced the ability of NHS i1 to rescue migration persistence. Using Tandem Affinity Purification (TAP) of NHS i1 and mass spectrometry, we identified as major NHS partners, all subunits of the WAVE Regulatory Complex (WRC) except WAVE subunits themselves, indicating that the WHD of NHS assembles a WAVE Shell Complex (WSC). The Arp2/3 complex and the Nucleation Promoting Factor (NPF) WAVE that activates it are critical for migration persistence. To investigate the role of the NHS-containing WSC, we performed TAP of the ABI1 subunit in parental and NHS KO cells and identified differential partners associated with ABI1 only in parental cells, but not in NHS KO cells. The most abundant of these were the WIPF2/N-WASP complex, which together with the kinase ABL2, was also critical for migration persistence. These results suggest that NHS controls cell migration by remodeling NPF complexes and their higher order assembly.
SN - 0021-9258
SN - 1083-351X
ER -