Biology subjects

Eisler, S. A.

Publications and source records attributed to Eisler, S. A..

6 recordsLinked to original sources

bioRxiv2026

Interplay between β-catenin transcriptional and cell-cell junction activity regulates homeostasis and collective dynamics in the intestinal epithelium

Wnt signaling is crucial for stem cell maintenance during development and homeostasis, and its dysregulation is implicated in cancers across multiple tissues. {beta}-catenin, the primary mediator of canonical Wnt signaling, is also a crucial adaptor protein at cell-cell junctions and is required for maintaining tissue integrity. How the interplay and potential competition between these discrete functions of {beta}-catenin influences tissue homeostasis and organization is not well understood. Here, we address this open question in the intestinal epithelium, which is highly dependent on Wnt signaling during homeostasis and regeneration. Ectopic activation of Wnt signaling in intestinal organoids by pharmacological or genetic perturbation leads to tissue fluidification and loss of epithelial integrity, while disrupting Wnt activity perturbs intracellular {beta}-catenin localization and dynamics at cell-cell junctions. Stabilization of cell-cell junctions increases {beta}-catenin accumulation at junctions at the expense of nuclear localization, while junctional perturbation leads to {beta}-catenin release from junctions into the cytoplasm, leading to dysregulation of Wnt signaling. Together, our findings indicate that in tissues with active Wnt signaling, the interplay between junction- and signaling-associated {beta}-catenin is crucial for stem cell regulation and tissue homeostasis.

cell biology↗

bioRxiv2026

Mechanosensing and IL-13 Signaling Synergistically Modulate Intestinal Stem Cell Differentiation via STAT6 and YAP

A long-term complication of chronic inflammation is the mechanical stiffening of the tissue, culminating in fibrosis. Fibrosis can severely disrupt tissue function and is a major risk factor for other diseases. It is not currently well understood how fibrosis impacts the response to inflammatory signals. To address this, we investigated cross-talk between cellular mechanosensing and the response to Interleukin (IL)-13, a cytokine associated with inflammatory bowel diseases (IBDs). Using 3D intestinal organoids and organoid monolayer culture, we uncovered a synergy between mechanosensing and IL-13 signaling in regulating intestinal stem cell differentiation. Through quantitative high-resolution microscopy and functional inhibition, we found that this response requires activation of STAT6, a known mediator of IL-13. Both IL-13 and high substrate stiffness increase cellular traction forces and focal adhesion formation, but at the expense of reduced tension at cell-cell junctions and compromised epithelial barrier function. The mechanosensing and IL-13 responses require actomyosin contractility and YAP, which is activated downstream of a positive feedback loop involving STAT6-dependent myosin-2 activation. Our results establish a novel STAT6-YAP signaling axis that integrates inflammatory and mechanical cues to regulate intestinal cell fate and barrier integrity, opening new avenues to target epithelial dysfunction in fibrosis, chronic inflammation and regenerative medicine.

cell biology↗

bioRxiv2022

PKD autoinhibition in trans regulates activation loop autophosphorylation in cis

Phosphorylation is a ubiquitous mechanism by which signals are transduced in cells. Protein kinases, enzymes that catalyze the phospho-transfer reaction are, themselves, often regulated by phosphorylation. Paradoxically, however, a substantial fraction of the more than 500 human protein kinases are capable of catalyzing their own activation loop phosphorylation. Commonly, these kinases perform this autophosphorylation reaction in trans, whereby transient dimerization leads to the mutual phosphorylation of the activation loop of the opposing protomer. In this study, we demonstrate that Protein Kinase D (PKD) is regulated by the inverse mechanism of dimerization-mediated trans-autoinhibition, followed by activation loop autophosphorylation in cis. We show that PKD forms a stable face-to-face homodimer that is incapable of either auto- or substrate phosphorylation. Dissociation of this trans-autoinhibited dimer results in activation loop autophosphorylation, which occurs exclusively in cis. Phosphorylation serves to increase PKD activity and prevent trans-autoinhibition, thereby switching PKD on. Our findings not only reveal the mechanism of PKD regulation, but have profound implications for the regulation of many other eukaryotic kinases.

biochemistry↗

bioRxiv2022

The GEF-GAP pair Solo and DLC3 balances Rho activity during endocytic transport

The control of intracellular membrane trafficking by Rho GTPases is central to cellular homeostasis. How defined pairs of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) come together to locally balance GTPase activation cycles in this process is nevertheless largely unclear. By performing a microscopy-based RNAi screen we here identify the RhoGEF protein Solo as a counterpart of DLC3, a RhoGAP protein with established roles in membrane trafficking. Biochemical, imaging and optogenetics assays further uncover Solo as a novel regulator of endosomal RhoB. Remarkably, we find that the interplay between Solo and DLC3 controls not only the activity but also total protein levels of RhoB. Together, the results of our study uncover the first functionally connected RhoGAP-RhoGEF pair at endomembranes and place the Solo-DLC3 axis at the core of endocytic trafficking.

cell biology↗

bioRxiv2021

Cell-to-cell heterogeneities during extrinsic apoptosis arise from cell cycle progression and transmitotic apoptosis resistance

Extrinsic apoptosis relies on TNF-family receptor activation by immune cells or receptor-activating biologics. Here, we monitored cell cycle progression at minutes resolution to relate apoptosis kinetics and cell-to-cell heterogeneities in death decisions to cell cycle phases. Interestingly, we found that cells in S phase delay TRAIL receptor-induced death in favour for mitosis, thereby passing on an apoptosis-primed state to their offspring. This translates into two distinct fates, apoptosis execution post mitosis or cell survival from inefficient apoptosis. Transmitotic resistance is linked to Mcl-1 upregulation from mid S phase onwards, which allows cells to pass through mitosis with activated caspase-8, and with cells escaping apoptosis after mitosis sustaining sublethal DNA damage. Antagonizing Mcl-1 by BH3-mimetics suppresses cell cycle-dependent delays in apoptosis, prevents apoptosis-resistant progression through mitosis and averts unwanted survival from apoptosis induction. Cell cycle progression therefore modulates signal transduction during extrinsic apoptosis, with Mcl-1 governing decision making between death, proliferation and survival from inefficient apoptosis induction. Cell cycle progression thus is a crucial process from which cell-to-cell heterogeneities in fates and treatment outcomes emerge in isogenic cell populations during extrinsic apoptosis signalling.

cell biology↗

bioRxiv2020

PKD promotes activity-dependent AMPA receptorendocytosis in hippocampal neurons

AMPA type glutamate receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the brain. The continuous trafficking of AMPARs into and out of synapses is a core feature of synaptic plasticity, which is considered as the cellular basis of learning and memory. The molecular mechanisms underlying the postsynaptic AMPAR trafficking, however, are still not fully understood. In this work, we demonstrate that the Protein Kinase D (PKD) family promotes basal and activity-induced AMPAR endocytosis in primary hippocampal neurons. Pharmacological inhibition of PKD increased synaptic levels of GluA1-containing AMPARs, slowed down their endocytic trafficking and increased neuronal network activity. By contrast, ectopic expression of constitutive active PKD decreased the synaptic level of AMPARs, while increasing their co-localization with early endosomes. Our results thus establish an important role for PKD in the regulation of postsynaptic AMPAR trafficking during synaptic plasticity.

neuroscience↗