Novikov Nikita M, Gao Jinmei, Fokin Artem I, Rocques Nathalie, Chiappetta Giovanni, Rysenkova Karina D, Zea Diego Javier, Polesskaya Anna, Vinh Joelle, Guerois Raphael, Gautreau Alexis M
Laboratory of Structural Biology of the Cell (BIOC), CNRS UMR7654, École Polytechnique, Institut Polytechnique de Paris, Palaiseau, France.
Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France.
Nat Commun. 2025 Jan 2;16(1):205. doi: 10.1038/s41467-024-55647-3.
The molecular mechanisms underlying cell migration remain incompletely understood. Here, we show that knock-out cells for NHSL3, the most recently identified member of the Nance-Horan Syndrome family, are more persistent than parental cells in single cell migration, but that, in wound healing, follower cells are impaired in their ability to follow leader cells. The NHSL3 locus encodes several isoforms. We identify the partner repertoire of each isoform using proteomics and predict direct partners and their binding sites using an AlphaFold2-based pipeline. Rescue with specific isoforms, and lack of rescue when relevant binding sites are mutated, establish that the interaction of a long isoform with MENA/VASP proteins is critical at cell-cell junctions for collective migration, while the interaction of a short one with 14-3-3θ in lamellipodia is critical for single cell migration. Taken together, these results demonstrate that NHSL3 regulates single and collective cell migration through distinct mechanisms.
细胞迁移背后的分子机制仍未完全明确。在此，我们表明，Nance-Horan综合征家族中最新鉴定出的成员NHSL3的基因敲除细胞在单细胞迁移中比亲代细胞更具持续性，但在伤口愈合过程中，跟随细胞跟随引导细胞的能力受损。NHSL3基因座编码几种异构体。我们使用蛋白质组学鉴定每种异构体的相互作用蛋白库，并使用基于AlphaFold2的流程预测直接相互作用蛋白及其结合位点。用特定异构体进行拯救实验，以及当相关结合位点发生突变时无法拯救，证实了一种长异构体与MENA/VASP蛋白的相互作用在细胞-细胞连接处对集体迁移至关重要，而一种短异构体与片状伪足中的14-3-3θ的相互作用对单细胞迁移至关重要。综上所述，这些结果表明NHSL3通过不同机制调节单细胞和集体细胞迁移。
