Biology subjects

Pednekar, C.

Publications and source records attributed to Pednekar, C..

6 recordsLinked to original sources

bioRxiv2026

mTORC2 stabilizes HIF-1β to coordinate metabolic adaptation in lung cancer

Despite extensive genetic heterogeneity, lung tumors frequently converge on shared signaling dependencies that remain therapeutically underexploited. Here, we identify mTORC2 signaling as a convergent dependency across genetically distinct lung cancer subtypes and uncover HIF-1{beta} as a selective metabolic effector downstream of mTORC2 that promotes lung tumor progression. Elevated mTORC2 signaling in lung adenocarcinoma was associated with poor overall survival, metastatic dissemination and metabolic rewiring. Using complementary genetically engineered mouse models of Rictor deletion or overexpression in Kras-driven lung tumors, we show that mTORC2 activity is dispensable for normal lung homeostasis but required for tumor progression and metabolic adaptation in vivo. Mechanistically, mTORC2 stabilized HIF-1{beta} by preventing its ubiquitin-independent proteasomal degradation through a non-canonical PKC-CK2 signaling axis, independently of AKT. Integrated multi-omics analyses identified extensive metabolic rewiring downstream of the mTORC2-HIF-1{beta} axis, with sphingolipid metabolism emerging as a prominent and therapeutically exploitable vulnerability. Accordingly, pharmacological targeting of sphingolipid metabolism markedly impaired the growth of mTORC2-driven lung tumors in vivo. Together, our findings establish a non-canonical mTORC2-HIF-1{beta} signaling axis that couples oncogenic signaling to metabolic adaptation and defines therapeutically actionable metabolic vulnerabilities in lung cancer.

cancer biology↗

bioRxiv2026

Ubiquitin recognition integrates plant immune signaling by cell-surface and intracellular receptors

Plant immunity is activated by cell-surface and intracellular receptors that detect pathogen-derived molecules. Mutual potentiation between these two receptor types is essential for robust disease resistance, but the mechanisms underpinning integrated dual receptor immunity remain unknown. Here, we found that activation of the intracellular receptor, ZAR1, induces its site-specific modification by non-proteolytic ubiquitin chains. ZAR1-anchored ubiquitin chains promote oligomerization of ZAR1 into a calcium-permeable resistosome pore and are recognized by RH3, a ubiquitin-binding DEAD-box RNA helicase. Remarkably, RH3 recruits both ZAR1 resistosomes and cell-surface receptor components into a dual receptor complex, thereby enhancing calcium-dependent mRNA translation of core defense proteins and establishing robust immunity. These findings identify ubiquitin recognition as the missing link in mutual potentiation of plant immunity by cell-surface and intracellular receptors.

plant biology↗

bioRxiv2025

ER-liquid condensate contacts sequester FAM134B/C and RhoA to govern cell morphology

ER-phagy receptors have elusive physiological functions beyond ER remodelling. Here, we use proximity biotinylation to identify their cytoplasmic interactomes. Secondary CRISPR/Cas9 screening reveals regulators of the prototypical FAM134B/C receptors, which include PRKAR1A, canonically known as a subunit of PKA. PRKAR1A directly binds an amphipathic helix in the otherwise disordered cytoplasmic domain of FAM134B. Super-resolution, FRAP and CLEM imaging reveal novel interorganellar contacts between liquid-like condensates of cAMP-bound PRKAR1A and the ER. Condensates promote clustering of ER-embedded FAM134B/C with LC3B, independently of regulation of PKA by PRKAR1A. Proteomics reveal that cytoplasmic RhoA interacts with FAM134B/C clusters and that sequestration of both these molecules occurs within lysosomes embedded within the proximal condensates. This results in reduced actomyosin contractility and ER-condensate interactions thusly determine cell morphology and cancer cell invasion modality. In summary, ER-condensate contacts mediated by FAM134B/C are novel cellular degradation hubs that coordinate ER and cellular remodelling.

cell biology↗

bioRxiv2025

JMJD5 regulates metabolism by inhibiting the Arginine Methyltransferase PRMT6

2-Oxoglutarate-dependent dioxygenases (2OGDDs) employ molecular oxygen, 2-oxoglutarate, and ferrous iron to catalyse two-ectron oxidations. This dependency enables some 2OGDD to act as sensors of cellular metabolic states, driving crucial functions when oxygen or metabolic homeostasis is perturbed, including adaptation to low oxygen, epigenetic control of gene transcription, and the reshaping of metabolic pathways. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), a 2OGDD that regulates epigenetic marks, is essential for DNA damage repair and is a key regulator of cell metabolism. Notably, JMJD5 is often reduced in hepatocellular carcinoma, correlating with poor overall survival. Despite its biological significance, the molecular functions of JMJD5 remain unresolved, and its physiological targets are elusive. Here, we identify and characterise a novel signalling pathway where JMJD5 hydroxylates an arginine residue on the protein ISY1. This modification enables ISY1 to bind to and reduce the activity of Protein Arginine N-methyltransferase 6 (PRMT6). Significantly, the inactivation of PRMT6 rescues the majority of the molecular phenotype driven by JMJD5 loss, establishing the JMJD5-ISY1-PRMT6 pathway as a principal executor of JMJD5s enzymatic function. In a genetically engineered murine liver cancer model, JMJD5 loss suppressed tumour growth and rewired one-carbon, amino acid, and lipid metabolism, recapitulating the network-level changes observed in human HCC cells. This signalling pathway clarifies existing controversies regarding JMJD5s function and identifies PRMT6 as a potential therapeutic target for treating cancers that lack JMJD5.

cell biology↗

bioRxiv2025

H2AK119ub Safeguards Against Ectopic Transcription Factor Mediated Gene Activation in the Developing Forebrain

The PRC1 complex regulates developmental gene expression in mammals by ubiquitinating histones (H2AK119ub) and nucleating repressive chromatin interactions. Human genetic data and functional experimentation have demonstrated that H2AK119ub is required for cortical development, however the molecular mechanism for this remains unknown. Here, we show that mouse embryos expressing catalytically deficient RING1B exhibit intact early neurogenesis but display impaired neuroectodermal fate restriction. Using in vivo, primary, and in vitro models, we demonstrate that reduced H2AK119ub leads to ectopic activation of lineage-inappropriate transcriptional programmes, including mesodermal and endodermal gene expression during neural differentiation. This transcriptional deregulation is not solely attributable to H2AK119ub or H3K27me3 loss but instead reflects sensitisation of PRC1 target genes to inappropriate transcription factor (TF)-mediated activation. Synthetic induction of candidate TFs, including GATA6, SOX7, and SNAI1, phenocopies the fate-skewing effects of PRC1 catalytic dysfunction, confirming their causal role. Our results uncover a buffering role for PRC1-catalysed H2AK119ub in safeguarding neural progenitor identity by preventing inappropriate TF-driven transcription and provides a mechanistic framework for understanding the cellular heterogeneity and phenotypic variability observed in Polycomb-associated neurodevelopmental disorders.

molecular biology↗

bioRxiv2024

FAK modulates glioblastoma stem cell energetics via actomyosin contractility: regulation of glycolysis and mitochondrial function

Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). We show that focal adhesion kinase (FAK), a mediator of integrin-ECM signalling, is driving cellular energetics in a stem cell model of glioblastoma (GBM). FAK gene deletion inhibits both glycolysis and glutamine oxidation, with increased mitochondrial fragmentation and elevated phosphorylation of the mitochondrial protein MTFR1L at S235. Simultaneously, FAK loss causes a mesenchymal to epithelial transition, enhanced acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19) and impaired cell migration/invasiveness. Rho-kinase (ROCK) inhibitors suppress p-MLC (S19) and restore glutamine oxidation and elongation of mitochondria. Thus, FAK is a key regulator of both glycolysis and glutamine oxidation mediated by acto-myosin contractility that controls both cell and mitochondrial morphology. Moreover, FAK-dependent cellular energetics are coincident properties with GBM stem cell migration, invasiveness and tumour growth in vivo.

cancer biology↗