About

William M. Brieher is a Professor in the Department of Cell and Developmental Biology at the University of Illinois. He earned his Ph.D. from the University of California, San Francisco, and completed postdoctoral training at Harvard Medical School. His research focuses on the cytoskeleton and cell adhesion, specifically investigating how cells organize the actin cytoskeleton. His lab studies the assembly and disassembly of actin filaments at cell-cell adhesive junctions and the signaling mechanisms that trigger actin assembly. These fundamental processes are critical for understanding cell shape, motility, and morphogenesis. Additionally, some of his research provides insights into the molecular basis of inherited kidney disease. Professor Brieher employs a combination of biochemical, biophysical, and cell biological techniques to address these questions. He has been recognized with the LAS Dean's Award for Excellence in Undergraduate Teaching.

Research topics

• Biology
• Cell biology
• Biochemistry
• Chemistry
• Biophysics
• Genetics
• Materials science
• Nanotechnology

Selected publications

• ATP-dependent actin barbed-end fluctuations at steady state

  Proceedings of the National Academy of Sciences · 2025-11-20

  articleOpen accessSenior authorCorresponding

  Actin networks in cells are dynamic and constantly turning over as actin subunits exchange between monomer and polymer pools. Understanding these dynamics in vivo requires a detailed understanding of pure actin behavior in vitro. The prevailing model is treadmilling, which predicts continuous growth of filament barbed ends balanced by continuous shrinkage of pointed ends, while filament length remains roughly constant. While treadmilling has been observed directly at the level of single filaments, length fluctuations-expressed as "length diffusivity"-are much greater than expected, and the origin of these high diffusivity values could not be identified experimentally. By imaging single filaments tethered to glass via α-actinin, we observed frequent, low-amplitude barbed-end fluctuations of ±2-6 subunits per event and rarer, high-amplitude fluctuations of ±50-150 subunits per event. Barbed-end fluctuations depended on adenosine triphosphate (ATP) hydrolysis and release of inorganic phosphate (Pi) and were blocked by phalloidin and barbed-end capping agents. Barbed-end fluctuations consumed an estimated one-third of the ATP at steady state, while two-thirds is still consumed by treadmilling. Fluctuations result in diffusive spreading of filament lengths that exceeds predictions from pure treadmilling yet is lower than previously reported values, suggesting that earlier measurements captured additional sources of variability. Our results provide direct experimental evidence for kinetic models that proposed a dampened form of dynamic instability in pure actin where transient loss of the ATP/ADP•Pi barbed-end cap leads to rare, large excursions superimposed on more frequent, small fluctuations.

  PublisherDOI

• Cell Deformation Signatures along the Apical-Basal Axis: A 3D Continuum Mechanics Shell Model.

  PubMed · 2025-01-29

  preprintOpen access

  Two-dimensional (2D) mechanical models of confluent tissues have related the mechanical state of a monolayer of cells to the average perimeter length of the cell cross sections, predicting floppiness or rigidity of the material. For the well-studied system of in-vitro MDCK epithelial cells, however, we find experimentally that cells in mechanically rigid tissues display long perimeters characteristic of a floppy state in 2D models. We suggest that this discrepancy is due to mechanical effects in the third (apical-basal) dimension, including those caused by actin stress fibers near the basal membrane. To quantitatively understand cell deformations in 3D, we develop a continuum mechanics model of epithelial cells as elastic cylindrical shells, with appropriate boundary conditions reflecting both the passive confinement of neighboring cells and the active stress of actomyosin contractility. This formalism yields analytical solutions predicting cell cross sections along the entire cylinder axis. Deconvolution microscopy experimental data confirm the significant and systematic change in cell shape parameters in this apical-basal direction. In addition to providing a wealth of detailed information on deformation on the subcellular scale, the results of the approach alter our understanding of how active tissues balance requirements of their stiffness and integrity, suggesting they are more robust against loss of rigidity than previously inferred.

  PublisherOA PDF

• BPS2025 – Steady-state actin filaments undergo ATP-dependent, barbed end-length fluctuations

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• Corrigendum: Revisiting bacterial cytolethal distending toxin structure and function

  Frontiers in Cellular and Infection Microbiology · 2024-01-16

  erratumOpen access

  [This corrects the article DOI: 10.3389/fcimb.2023.1289359.].

  PublisherOA PDFDOI

• Revisiting bacterial cytolethal distending toxin structure and function

  Frontiers in Cellular and Infection Microbiology · 2023-11-14 · 3 citations

  articleOpen access

  Cytolethal distending toxins (CDTs) are intracellular-acting bacterial genotoxins generated by a diverse group of mucocutaneous human pathogens. CDTs must successfully bind to the plasma membrane of host cells in order to exert their modulatory effects. Maximal toxin activity requires all three toxin subunits, CdtA, CdtB, and CdtC, which, based primarily on high-resolution structural data, are believed to preassemble into a tripartite complex necessary for toxin activity. However, biologically active toxin has not been experimentally demonstrated to require assembly of the three subunits into a heterotrimer. Here, we experimentally compared concentration-dependent subunit interactions and toxin cellular activity of the Campylobacter jejuni CDT ( Cj -CDT). Co-immunoprecipitation and dialysis retention experiments provided evidence for the presence of heterotrimeric toxin complexes, but only at concentrations of Cj- CdtA, Cj- CdtB, and Cj- CdtC several logs higher than required for Cj- CDT-mediated arrest of the host cell cycle at the G 2 /M interface, which is triggered by the endonuclease activity associated with the catalytic Cj- CdtB subunit. Microscale thermophoresis confirmed that Cj -CDT subunit interactions occur with low affinity. Collectively, our data suggest that at the lowest concentrations of toxin sufficient for arrest of cell cycle progression, mixtures of Cj- CdtA, Cj -CdtB, and Cj -CdtC consist primarily of non-interacting, subunit monomers. The lack of congruence between toxin tripartite structure and cellular activity suggests that the widely accepted model that CDTs principally intoxicate host cells as preassembled heterotrimeric structures should be revisited.

  PublisherOA PDFDOI

• Abstract 2389: Profilin augments Cofilin induced Actin dynamics

  Journal of Biological Chemistry · 2023-01-01

  articleOpen accessSenior author
  PublisherDOI

• Synaptopodin stress fiber and contractomere at the epithelial junction

  The Journal of Cell Biology · 2022-02-10 · 12 citations

  articleOpen access

  The apical junction of epithelial cells can generate force to control cell geometry and perform contractile processes while maintaining barrier function and adhesion. Yet, the structural basis for force generation at the apical junction is not fully understood. Here, we describe two synaptopodin-dependent actomyosin structures that are spatially, temporally, and structurally distinct. The first structure is formed by the retrograde flow of synaptopodin initiated at the apical junction, creating a sarcomeric stress fiber that lies parallel to the apical junction. Contraction of the apical stress fiber is associated with either clustering of membrane components or shortening of junctional length. Upon junction maturation, apical stress fibers are disassembled. In mature epithelial monolayer, a motorized "contractomere" capable of "walking the junction" is formed at the junctional vertex. Actomyosin activities at the contractomere produce a compressive force evident by actin filament buckling and measurement with a new α-actinin-4 force sensor. The motility of contractomeres can adjust junctional length and change cell packing geometry during cell extrusion and intercellular movement. We propose a model of epithelial homeostasis that utilizes contractomere motility to support junction rearrangement while preserving the permeability barrier.

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• Synaptopodin is required for stress fiber and contractomere assembly at the epithelial junction

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-01-01 · 1 citations

  preprintOpen access

  Abstract The apical junction of epithelial cells can generate force to control cell geometry and perform contractile processes while maintaining barrier function and adhesion. Yet, the structural basis for force generation at the apical junction is not fully understood. Here, we describe 2 synaptopodin-dependent actomyosin structures that are spatially, temporally, and structurally distinct. The first structure is formed by retrograde flow of synaptopodin initiated at the apical junction, creating sarcomeric stress fibers that lie parallel to the junction and insert into junctional complexes on the apical plane. Retrograde flow of synaptopodin is also seen at vinculin-decorated basal junctions on the basal plane. Contractions of apical stress fibers is associated with clustering of membrane complexes via side-on synaptopodin linkers whereas contractions of stress fibers inserted at the apical junction via head-on synaptopodin linkers results in junction shortening. Upon junction maturation, apical stress fibers are disassembled. In mature epithelial monolayer, a motorized “contractomere” complex capable of “walking the junction” is formed at junction vertices. Contractomere motility results in changes in junctional length, altering the overall shape of the cell and packing geometry within the monolayer. We propose a model of epithelial homeostasis that utilizes contractomere motility to preserve the permeability barrier during intercellular movement and junctional processes. Summary Statement Synaptopodin retrograde flows initiate the assembly of apical and basal stress fibers from the apical and basal junctions. In mature apical junction, a motorized junctional complex, we termed the contractomere, allows the apical junction to change length and organize cell geometry within a confluent monolayer.

  PublisherOA PDFDOI

• Cadherin puncta are interdigitated dynamic actin protrusions necessary for stable cadherin adhesion

  Proceedings of the National Academy of Sciences · 2021 · 37 citations

  Senior authorCorresponding
  • Cell biology
  • Biophysics
  • Chemistry

  Cadherins harness the actin cytoskeleton to build cohesive sheets of cells using paradoxically weak bonds, but the molecular mechanisms are poorly understood. In one popular model, actin organizes cadherins into large, micrometer-sized clusters known as puncta. Myosin is thought to pull on these puncta to generate strong adhesion. Here, however, we show that cadherin puncta are actually interdigitated actin microspikes generated by actin polymerization mediated by three factors (Arp2/3, EVL, and CRMP-1). The convoluted membranes in these regions give the impression of cadherin clustering by fluorescence microscopy, but the ratio of cadherin to membrane is constant. Nevertheless, these interlocking fingers of membrane are important for adhesion because perturbing their formation disrupts cell adhesion. In contrast, blocking myosin-dependent contractility does not disrupt either the interdigitated microspikes or lateral membrane adhesion. "Puncta" are zones of strong cell-cell adhesion not due to cadherin clustering but that occur because the interdigitated microspikes expand the surface area available for adhesive bond formation and increase the asperity of the cell surface to promote friction between cells.

  PublisherOA PDFDOI

• Interdigitated dynamic actin protrusions maintain stable cadherin adhesion

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-10-12

  preprintOpen accessSenior author

  Abstract Cadherins build stable, cohesive sheets of cells using paradoxically weak bonds. Actin is thought to convert weak binding into strong adhesion either by transmitting myosin dependent pulling forces to adhesive junctions or by clustering cadherins in the plane of the membrane. Here, however, we show that continuous actin polymerization stabilizes cadherin adhesion by directly driving membrane protrusions, not by promoting contractility or cadherin clustering. Lateral membranes of epithelial cells are continuously pushed against each another by protrusions. Micrometer sized cadherin puncta, long thought to be clusters of cadherins, turn out to be patches of microspikes interlocked by cadherin homophilic bonds to hold neighboring cells together. When actin polymerization is blocked, protrusions cease, puncta disappear, and lateral membranes detach from one another. In contrast, inhibiting myosin II contractility has no effect on adhesion. One Sentence Summary Stronger together: membrane interdigitations keep cells attached.

  PublisherOA PDFDOI

Recent grants

• Actin Assembly at Cadherin Dependent Adherens Junctions

  NIH · $2.3M · 2013–2024

• Actin Assembly at Cadherin Dependent Adherens Junctions

  NIH · $285k · 2013–2018

Frequent coauthors

• Timothy J. Mitchison

  Harvard University

  23 shared

• Hao Yuan Kueh

  University of Washington

  16 shared

• Barry M. Gumbiner

  University of Virginia

  16 shared

• Tadeusz Majewski

  The University of Texas MD Anderson Cancer Center

  13 shared

• Guillaume Charras

  University College London

  13 shared

• George Flouret

  12 shared

• Vivian Tang

  11 shared

• Laird Wilson

  10 shared

Labs

• Cytoplasmic Structure and DynamicsPI

Awards & honors

• LAS Dean's Award for Excellence in Undergraduate Teaching