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  • Review Article
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Cell–cell interfaces as specialized compartments directing cell function

Abstract

Cell–cell interfaces are found throughout multicellular organisms, from transient interactions between motile immune cells to long-lived cell–cell contacts in epithelia. Studies of immune cell interactions, epithelial cell barriers, neuronal contacts and sites of cell–cell fusion have identified a core set of features shared by cell–cell interfaces that critically control their function. Data from diverse cell types also show that cells actively and passively regulate the localization, strength, duration and cytoskeletal coupling of receptor interactions governing cell–cell signalling and physical connections between cells, indicating that cell–cell interfaces have a unique membrane organization that emerges from local molecular and cellular mechanics. In this Review, we discuss recent findings that support the emerging view of cell–cell interfaces as specialized compartments that biophysically constrain the arrangement and activity of their protein, lipid and glycan components. We also review how these biophysical features of cell–cell interfaces allow cells to respond with high selectivity and sensitivity to multiple inputs, serving as the basis for wide-ranging cellular functions. Finally, we consider how the unique properties of cell–cell interfaces present opportunities for therapeutic intervention.

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Fig. 1: A brief history of cell–cell interfaces.
Fig. 2: Examples of cell–cell interfaces and their shared components.
Fig. 3: Biophysical features of cell–cell interfaces shaped by the membrane.
Fig. 4: Regulation of interfacial processes by mechanical forces and biomolecular condensates.

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Acknowledgements

The authors thank E. Schmid for her research contributions and guidance on this Review, and the Fletcher and Dustin laboratories for helpful discussions. B.B. was supported by the National Institutes of Health (NIH) Ruth L. Kirschstein NRSA fellowship from the NIH (1F32GM115091). S.S. was supported by the Life Science Research Foundation. J.H.F. and M.L.D. were supported by the Wellcome Trust. This work was supported in part by the NIH R01 GM114671 (D.A.F.), the Immunotherapeutics and Vaccine Research Initiative at UC Berkeley (D.A.F.), the Miller Institute for Basic Research (D.A.F.), the NSF Center for Cellular Construction (DBI-1548297) and the Chan Zuckerberg Biohub (D.A.F.).

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Supplementary information

Glossary

Myoblast

A mononucleated, undifferentiated muscle cell precursor.

Tight junctions

Cell–cell junctions that seal adjacent epithelial cells together, preventing the passage of most dissolved molecules from one side of the epithelial sheet to the other.

Physical boundary conditions

A set of constraints that define a closed physical system.

Desmosomes

Anchoring cell–cell junctions, usually formed between two epithelial cells, characterized by dense plaques of protein into which intermediate filaments in the two adjoining cells insert.

Integrins

A large family of transmembrane proteins, consisting of α and β-subunits, involved in the adhesion of cells to the extracellular matrix and to each other.

Glycocalyx

A carbohydrate-rich layer that forms the outer coat of a eukaryotic cell, composed of the oligosaccharides linked to plasma membrane glycoproteins and glycolipids, as well as glycoproteins and proteoglycans that have been secreted and reabsorbed onto the cell surface.

Natural killer cells

Cytotoxic cells of the innate immune system that can kill virus-infected and cancer cells.

Antigen-presenting cells

Highly specialized cells that can process antigens and display their peptide fragments on the cell surface together with other, co-stimulatory, proteins required for activating naive T cells.

Adherens junction

A cell–cell interface that holds neighbouring cells together through transmembrane cadherin family proteins. The cytoplasmic face of the junction is attached to actin filaments. Examples include the adhesion belts linking adjacent epithelial cells.

Ideal bond

A bond whose lifetime is not influenced by force.

Slip bond

A bond whose lifetime is shortened under force.

Catch bond

A bond that increases its lifetime under force.

Kinetic trap

A system trapped in a local energy minimum of an energetic landscape due to high-energy transition barriers.

Enthalpy

A thermodynamic quantity equivalent to the sum of the system’s internal energy and the product of its pressure and volume.

Entropy

A thermodynamic quantity that measures the degree of disorder in a system.

Cell cortex

A thin network of actin filaments and actin-binding proteins that underlies the plasma membrane in most eukaryotic cells.

α-Catenin

An adaptor protein of the adherens junction that is part of the E-cadherin–catenin complex and can bind to the actin cytoskeleton.

Vinculin

An adaptor protein of both the adherens junction and focal adhesions that reinforces connections to the actin cytoskeleton.

Podosome

A dynamic, actin-rich cellular protrusion that degrades the extracellular matrix and is involved in cell invasion.

Wiscott–Aldrich syndrome protein

(WASP). A nucleation-promoting factor of the actin cytoskeleton that acts on the Arp2/3 complex.

Arp2/3 complex

A protein complex that nucleates the assembly of branched actin filament networks.

Biomolecular condensates

Membraneless compartments in cells that concentrate specific collections of proteins and nucleic acids into a dynamic assembly.

Liquid–liquid phase separation

The demixing of a fluid mixture into two distinct liquid phases.

Kinetic proofreading

A specificity mechanism in biochemical reactions that achieves high fidelity beyond what is possible by free-energy differences. In the immunological synapse, kinetic proofreading allows small differences in ligand binding half-life to be amplified into larger differences in signalling through intermediate steps.

Postsynaptic density

A protein-dense specialization in neurons attached to postsynaptic membranes.

Antibody-dependent cellular cytotoxicity

The killing of antibody-coated target cells by cells with Fc receptors that recognize the constant region of the bound antibody. Most antibody-dependent cellular cytotoxicity is mediated by natural killer cells that have the Fc receptor FcγRIII on their surface.

Chimeric antigen receptor

(CAR). Engineered fusion proteins composed of extracellular antigen-specific receptors (for example, single-chain antibody) and intracellular signalling domains that activate and co-stimulate, expressed in T cells for use in cancer immunotherapy.

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Belardi, B., Son, S., Felce, J.H. et al. Cell–cell interfaces as specialized compartments directing cell function. Nat Rev Mol Cell Biol 21, 750–764 (2020). https://doi.org/10.1038/s41580-020-00298-7

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