Biology subjects

Moreau, R.

Publications and source records attributed to Moreau, R..

5 recordsLinked to original sources

bioRxiv2026

Molecular glue degraders of CK1α remodel lysosomes and limit ferroptosis in glioblastoma stem-like cells

Glioblastoma stem-like cells (GSCs) are highly plastic tumor cells that drive initiation, progression and therapeutic resistance. Although lysosomal homeostasis has emerged as a critical determinant of GSC fitness, the molecular mechanisms regulating this compartment remain incompletely understood. Here, using complementary proteomic approaches, we identified a lysosomal signature associated with the kinase CK1 in THP1 monocytic cells. Biochemical analyses revealed that genetic or siRNA-mediated depletion of CK1 altered the overall abundance and maturation of late endosome-lysosome-associated proteins in both THP1 cells and two patient-derived GSCs. This lysosomal remodeling was associated with impaired tumorsphere formation capacity in GSCs. To further explore the therapeutic potential of targeting CK1, we employed selective molecular glue degraders (MGDs). Acute CK1 degradation efficiently recapitulated lysosomal remodeling and impaired tumorsphere formation in GSCs. While CK1-targeted MGDs did not sensitize GSCs to lysosomal membrane permeabilization induced by L-leucyl-L-leucine methyl ester (LLOMe), they protected from GPX4 inhibitor-induced ferroptosis. Together, these findings identify CK1 as a regulator of lysosomal fitness and ferroptotic sensitivity, suggesting a connection between CK1-dependent lysosome remodeling and associated cell death pathways.

cancer biology↗

bioRxiv2025

Linear ubiquitin chain assembly complex contributes to NLRP3-mediated pyroptotic cell death

Activation of the NLRP3 inflammasome by infectious or sterile insults culminates in pyroptosis, a lytic and highly inflammatory form of programmed cell death. A safeguarded two-step process tightly regulates pyroptosis: priming, which drives NF-{kappa}B signaling, followed by execution, ultimately leading to plasma membrane rupture. Linear (Met1-linked) ubiquitination, catalyzed by the E3 ligase complex LUBAC, was previously shown to participate in pyroptosis, but the underlying mechanisms are not fully understood. In this study, we show that Met1-linked ubiquitin chains can assemble during both priming and execution phases, independently of the inflammasome sensor NLRP3. Genetic deletion of the LUBAC enzymes or pharmacological inhibition impaired pyroptosis. Conversely, cell death was enhanced without the deubiquitinase OTULIN, which selectively removes linear ubiquitination. Finally, using an optogenetic model to bypass priming, we demonstrate that Met-1-linked ubiquitination is required for the execution phase of pyroptosis. These findings offer insights into the regulation of pyroptotic cell death by linear ubiquitination.

immunology↗

bioRxiv2025

The Kinase CK1α coordinates Initiation and Termination of the cGAS-STING Pathway

The cGAS-STING pathway is an evolutionarily conserved antimicrobial defense mechanism that senses cytosolic DNA to trigger innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using proteomic approaches, we report that Casein Kinase 1 alpha (CK1) operates as a bimodal regulator of the cGAS-STING pathway. CK1 supports optimal DNA sensing by preventing the proteasomal degradation of cGAS driven by the cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1 facilitates STING degradation and signaling termination in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1 with molecular-glue degraders impaired the survival of a triple-negative breast cancer cell line with chronic cGAS-STING activation and synergized with a STING agonist to kill acute myeloid leukemia cells. Thus, CK1s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development. TEASERThis study unveils CK1 as a bimodal regulator of the cGAS-STING pathway.

immunology↗

bioRxiv2024

Visual search efficiency is modulated by symmetry type and texture regularity

More than a century of vision research has identified symmetry as a fundamental cue, which aids the visual system in making inferences about objects and surfaces in natural scenes. Most studies have focused on one type of symmetry, reflection, presented at a single image location. However, the visual system responds strongly to other types of symmetries, and to symmetries that are repeated across the image plane to form textures. Here we use a visual search paradigm with arrays of repeating lattices that contained either reflection or rotation symmetries but were otherwise matched. Participants were asked to report the presence of a target tile without symmetry. When lattices tile the plane without gaps, they form regular textures. We manipulated texture regularity by introducing jittered gaps between lattices. This paradigm lets us investigate the effect of symmetry type and texture regularity on visual search efficiency. Based on previous findings suggesting an advantage for reflection in visual processing, we hypothesized that search would be more efficient for reflection than rotation. We further hypothesized that regular textures would be processed more efficiently. We found independent effects of symmetry type and regularity on search efficiency that confirmed both hypotheses: visual search was more efficient for textures with reflection symmetry and more efficient for regular textures. This provides additional support for the perceptual advantage of reflection in the context of visual search and provides important new evidence in favor of visual mechanisms specialized for processing symmetries in regular textures.

neuroscience↗

bioRxiv2021

Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer

Progressive fibrogenesis in chronic liver injury is often associated with cancer development. Beta-arrestin-2 (ARRB2) is a regulator of the profibrotic Angiotensin II type 1 receptor (AGTR1). The role of ARRB2 in liver fibrosis and in the transition from fibrosis to cancer is not fully understood and was investigated in this study. This study demonstrates that upregulation of the retinoic acid receptor responder 1 (RARRES1) in HSC mediated by ARRB2 leads to fibrosis. This process is driven by exosomal ARRB2 transfer to HSC, major fibrosis contributors, from injured hepatocytes, which highly express ARRB2. By contrast, downregulation of RARRES1 in hepatocytes induces malignant transformation and hepatocellular carcinoma (HCC) development. Consequently, Arrb2-deficient mice show higher number and size of liver tumors than wild-type mice in a hepatocellular carcinoma model with fibrosis. The identified relationship between ARRB2 and RARRES1 was observed in at least two species, including human cells and tissues in fibrosis and HCC and has a predictive value for survival in cancer patients. This study describes the discovery of a novel molecular pathway mediating the transition from fibrosis to cancer offering potential diagnostics and therapeutics.

molecular biology↗