Biology subjects

Englmaier, L.

Publications and source records attributed to Englmaier, L..

3 recordsLinked to original sources

bioRxiv2026

Inhibition of V-ATPase function drives apoptosis via GCN1/GCN2 kinase signaling

Natural products are a rich source of bioactive molecules that have served both as templates for drug discovery and as tools to uncover fundamental biological processes. While characterizing the pro-apoptotic activity of the cyanobacterial metabolite Nostatin A, we identified vacuolar-type H-ATPase (V-ATPase) as its molecular target and uncovered an unexpected signalling response preceding cell death initiation. V-ATPase inhibition rapidly activates the integrated stress response (ISR) through engagement of the GCN1/GCN2 kinase module, indicative of ribosomal collisions and translational shutdown. This response is conserved across established V-ATPase inhibitors, including bafilomycin A1, but not with compounds disrupting lysosomal function by other means. Mechanistically, V-ATPase inhibition depletes the pro-survival protein MCL-1 resulting in BAX/BAK-dependent mitochondrial apoptosis. Loss of MCL-1 creates a vulnerability that renders cells dependent on co-expressed BCL-2 family proteins, enabling potent synergy with the BH3 mimetics ABT-737 or venetoclax. Taken together, our results reveal a therapeutically exploitable vulnerability in V-ATPase-reliant or MCL-1 dependent cancers.

cell biology↗

bioRxiv2025

tRNA thiolation defects disrupt cellular proteostasis and tissue homeostasis in mammals

Sulfur modification of tRNA wobble uridines is an evolutionarily conserved mechanism that ensures efficient protein synthesis. In humans, loss of this anticodon modification due to mutations in CTU2 (cytosolic thiouridylase 2) causes DREAM-PL syndrome, a severe congenital disorder often leading to early postnatal death. However, the mechanisms by which loss of tRNA thiolation drives pathology remain unclear. Here, we show that loss of CTU2 triggers significant cellular proteostasis defects in patient cells and model cell lines. Structural and biochemical analyses reveal that the pathogenic CTU2L63P mutation destabilizes the CTU1/CTU2 complex and abolishes tRNA binding and thiolation. Acute loss of CTU2 caused codon-specific ribosome pausing at A-ending codons decoded by thiolated tRNAs, and decreased ribosome occupancy of A-rich transcripts in a dosage-dependent manner. Codon-biased mRNAs transcribed from genes critical for ciliogenesis are predicted to be most affected, linking their reduced translation to DREAM-PL etiology in humans. Surprisingly, Ctu2L63P mice display severe thiolation defects, but develop normally, are viable and fertile. Our findings highlight the importance of functional tRNA thiolation for organismal health in humans and identify species-specific vulnerabilities during embryonic development in mammals.

cell biology↗

bioRxiv2025

Photostimulation Improves Maturation of Human Photoreceptors

The human retina contains photoreceptor cells that detect light and enable vision. The development of these cells involves a tightly regulated cascade of structural and molecular events, and their dysfunction leads to irreversible blindness in many retinal diseases. Human retinal organoids derived from stem cells have become powerful tools to model retinal development and disease, but they often remain immature and lack key features required for full function. Light is not only the sensory target of photoreceptors but also an important developmental signal in vivo. However, light has rarely been used as a deliberate stimulus during in vitro differentiation. Here we show that exposing retinal organoids to rhythmic light flicker at a specific frequency enhances photoreceptor maturation across multiple levels. This stimulation improves the development of outer segments, accelerates the transcriptional transition from precursor to mature photoreceptors, and strengthens functional connectivity with downstream neurons. These findings identify patterned light as a potent and physiologically relevant signal for driving retinal development in vitro. This approach represents a non-invasive and easily scalable method for improving the quality of retinal organoids, with implications for disease modelling, drug discovery and the preparation of photoreceptors for cell-based therapies.

cell biology↗