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To nip an infection in the bud, immune cells must move quickly. Frontline responders such as neutrophils crawl, squeeze, and stretch their body to travel through environments made of meshwork-like substances, cramped intercellular channels, and other biological barriers.1 Their ability to circumvent physical obstruction, along with sensing and responding to other extracellular cues,2 is critical to reach their target destination.
Cells move by extending plasma membrane protrusions at their leading-edge, driven by the controlled polymerization of actin cytoskeletal filaments.3 When encountering obstacles, these curved formations undergo structural changes. Among the myriad proteins involved in membrane reshaping, Bin/Amphiphysin/Rvs (BAR) domain proteins have a distinctive ability to sense and modulate membrane curvature.4 In a recent study published in Nature Communications, scientists investigated whether they could play a part in prompting cells to change direction.5
Their tracks were really straight. It took us a while to understand what was happening.
–Alba Diz-Muñoz, European Molecular Biology Laboratory
“The role of BAR domain proteins in migration has not been explored a lot. And they have such a structurally interesting shape … like a banana. They really can take different levels of curvature,” said senior author Alba Diz-Muñoz, a cellular biophysicist at the European Molecular Biology Laboratory.
The researchers’ findings shed light on Sorting nexin 33 (SNX33), a poorly characterized BAR domain protein, highlighting it as a key player in neutrophil-like cell motility. For Etienne Morel, a cellular biologist at the Necker-Enfants Malades Institute who was not involved the study, this work elegantly connects different subfields of cell biology. “SNX proteins … are usually [studied] in membrane dynamics and intracellular membrane trafficking, not so much in cellular dynamics such as migration,” Morel said.
The team performed transcriptome profiling on both immature and differentiated neutrophil-like HL-60 cells,6 which are highly dynamic and rich in membrane protrusions. Of the 57 genes of interest encoding BAR domain proteins, the SNX33 gene had the most significant increase in expression after differentiation. Using CRISPR-Cas9 genome editing, the scientists knocked out SNX33 before performing cell migration assays. Compared to their normal counterparts, the deficient cells were less prone to make spontaneous turns.
“Their tracks were really straight. It took us a while to understand what was happening,” Diz-Muñoz said.
The researchers gained insight into this phenotype by exposing cells to both inert and live obstacles in vitro. Cells lacking SNX33 took 20% more time to navigate microfluidic channels of varying sizes. When densely seeded in a well, their length of contact with cells on their path increased, suggesting delayed decision-making.
Using molecular modeling, Diz-Muñoz's team observed that SNX33 preferentially bound to inward membrane curvatures. Consistent with this finding, they showed that in normal cells, the protein localized to the contact area, flattening upon collision. In contrast, a key regulator of actin assembly, Wiskott-Aldrich syndrome protein family verprolin-homologous protein-2 (WAVE2), relocated to contact-free zones, potentially promoting actin polymerization in a new direction. In the absence of SNX33, WAVE2 instead persisted at the site of contact, while actin filaments accumulated within the cell. These results, indicating uncontrolled actin polymerization, could explain why cells lacking SNX33 fail to appropriately change their trajectory. “When it’s not there, nobody tells the cell, hey, you hit something,” Diz-Muñoz said.
Overall, this study offers new insight into motility-dependent processes, such as collective cell migration to heal a wound or cancer cell dissemination to distant sites. It also raises new questions. According to Morel, if the plasma membrane is at the forefront of sensing obstacles, the whole cell is likely aware of it. He particularly questioned the role of the endomembrane system, a network of membranous structures within the cell involved in protein processing and transport, in trafficking SNX33 to specific plasma membrane regions.
Ultimately, other BAR domain proteins are on the team’s radar. Their diversity in shape and membrane binding affinity4 may help cells adapt to environmental changes through tailored reading of plasma membrane deformation. “This has to be such a fundamental process to keep your shape under control … that robustness is guaranteed by redundancy,” Diz-Muñoz concluded.
- Stramer B, et al. Mechanisms and in vivo functions of contact inhibition of locomotion. Nat Rev Mol Cell Biol. 2017;18(1):43-55.
- Berzat A, et al. Cellular responses to extracellular guidance cues. EMBO J. 2010;29(16):2734-2745.
- Ananthakrishnan R, et al. The forces behind cell movement. Int J Biol Sci. 2007;3(5):303-317.
- Simunovic M, et al. Curving cells inside and out: roles of BAR domain proteins in membrane shaping and its cellular implications. Annu Rev Cell Dev Biol. 2019;35:111-129.
- Sitarska E, et al. Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles. Nat Commun. 2023;14(1):5644.
- Collins SJ, et al. Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature. 1977;270(5635):347-349.
