Biology subjects

Mayor, F.

Publications and source records attributed to Mayor, F..

4 recordsLinked to original sources

bioRxiv2026

Gαq-mediated contact release is required for efficient mitochondrial quality control

Lysosomes and mitochondria are highly dynamic organelles whose coordinated interactions are essential for cellular homeostasis, while their dysfunction contributes to numerous human diseases. Here, we identify the mitochondrial outer membrane protein Fis1 and the RabGAPs TBC1D15 and TBC1D17 as novel interacting partners of the heterotrimeric G protein -subunit Gq. Using mitochondrial proteomics, co-immunoprecipitation, proximity ligation assays, and in vitro binding studies with purified proteins, we demonstrate that Gq forms a complex with Fis1 and TBC1D15/TBC1D17 through a non-canonical interaction interface. Gq localizes to mitochondria-lysosome contact sites, where it regulates the dynamic balance between contact formation and dissociation. Loss of Gq resulted in enlarged and clustered lysosomes and increased the extent and duration of mitochondria-lysosome contacts. Live-cell imaging revealed prolonged organelle tethering in Gq-deficient cells, while proximity ligation and three-dimensional reconstruction analyses localized Gq and TBC1D15 to mitochondrial tips closely associated with lysosomes. This localization, together with increased mitochondrial fission and altered mitophagic turnover following Gq loss, links the regulation of contacts at mitochondrial tips to mitochondrial fragmentation and quality control. Re-expression of Gq, but not the non-canonical interaction-deficient mutant, restored normal lysosomal morphology, contact-site dynamics, mitochondrial fragmentation, and mitophagy. Together, these findings identify a Gq as a dynamic regulator of mitochondria-lysosome untethering and connect contact site turnover with mitochondria fragmentation and mitophagy. Our work uncovers a novel link between G protein signaling, organelle communication, and mitochondrial quality control.

cell biology↗

bioRxiv2025

Loss of Gαq reshapes key fibroblast traits and drives matrix remodeling and aggressive progression of oral cancer tumors

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer, with limited therapeutic options and a high mortality rate, primarily due to metastasis and recurrence. Tumor-stroma interactions, and namely cancer-associated fibroblasts (CAFs), are pivotal in shaping HNSCC progression. CAFs remodel the extracellular matrix (ECM) and secrete factors and vesicles that promote tumor growth and metastasis. The interplay between autophagy and endosomal/exosomal pathways has been suggested to regulate cellular secretory functions, but their potential involvement in HNSCC progression remains poorly understood. Since we have recently uncovered Gq as a key modulator of autophagy, we have investigated the impact of Gq loss on fibroblast functionality and on its crosstalk with oral HNSCC cells. We report that the absence of Gq rewires murine embryonic fibroblasts towards CAF-like traits, leading to an increased pro-tumorigenic capacity of co-cultured human oral cancer cells through enhanced collagen I deposition and ECM remodeling. Strikingly, fibroblasts lacking Gq display a shift in the balance of intracellular trafficking, degradative and secretory pathways. Exosomes released from Gq-deficient fibroblasts show a marked enrichment in tumor-growth factor receptors and can facilitate aberrant tumor growth of HNSCC cells. Gq-silenced fibroblasts promote the formation of "railroad-tracks" structures around HNSCC cells, enhancing their migratory and invasive capabilities both in vitro and in vivo, and reduced Gq expression in human HNSCC CAFs correlates with enhanced tumor progression. Overall, our data put forward Gq as a key regulator of the HNSCC tumor microenvironment by modulating fibroblast plasticity and functionality.

cancer biology↗

bioRxiv2024

The G-Protein Couple Receptor Kinase 2 (GRK2) Orchestrates Hair Follicle Homeostasis

Tightly regulated cell-cell and cell-niche intercommunications via intertwined signaling networks are involved in maintaining normal hair follicle (HF) homeostasis, cycling and cell fate determination. However, knowledge of specific mechanisms by which hair loss takes place under pathological situations is needed. Using a keratinocyte-specific knockout mouse model, we uncover that the G-protein-coupled receptor kinase 2 (GRK2) signaling node plays a key role in HF homeostasis. Epidermal GRK2 ablation causes alterations during anagen induction, giving rise to abnormal cyst-like structures. HF-linked cysts display aberrant growth and differentiation patterns as well as lineage infidelity, displaying features of abortive HFs unable to fully acquire canonical hallmarks. Cysts triggered by GRK2 deletion displace the dermal papilla away from the bulge and promote irreversible changes in HF stem cell architecture, leading to bulge destruction and hair loss. Our data provide unforeseen roles of GRK2 in epidermal physiology and uncover mechanisms linking dystrophic follicular cysts formation with hair loss, with potential connections to pathogenic processes operating in immune-mediated alopecias.

cell biology↗

bioRxiv2024

GRK2-mediated AKT activation controls cell cycle progression and G2-checkpoint in a p53-dependent manner

Cell cycle checkpoints, activated by stressful events, halt the cell cycle progression, and prevent the transmission of damaged DNA. These checkpoints prompt cell repair but also trigger cell death if damage persists. Decision-making between these responses is multifactorial and context-dependent, with the tumor suppressor p53 playing a central role. In many tumor cells, p53 alterations lead to G1/S checkpoint loss, rendering cell viability dependent on the strength of the G2 checkpoint through mechanisms not fully characterized. Cells with a strong pro-survival drive can evade cell death despite substantial DNA lesions. Deciphering the integration of survival pathways with p53-dependent and -independent mechanisms governing the G2/M transition is crucial for understanding G2 arrest functionality and predicting tumor cell response to chemotherapy. The serine/threonine kinase GRK2 emerges as a signaling node in cell cycle modulation. In cycling cells, but not in G2 checkpoint-arrested cells, GRK2 protein levels decline during G2/M transition through a process triggered by CDK2-dependent phosphorylation of GRK2 at the S670 residue and Mdm2 ubiquitination. We report now that this downmodulation in G2 prevents the unscheduled activation of the PI3K/AKT pathway, allowing cells to progress into mitosis. Conversely, higher GRK2 levels lead to tyrosine phosphorylation by the kinase c-Abl, promoting the direct association of GRK2 with the p85 regulatory subunit of PI3K and AKT activation in a GRK2 catalytic-independent manner. Hyperactivation of AKT is conditioned by p53s scaffolding function, triggering FOXO3a phosphorylation, impaired cyclin B1 accumulation, and CDK1 activation, causing a G2/M transition delay. Upon G2 checkpoint activation, GRK2 potentiates early arrest independently of p53 through AKT activation. However, its ability to overcome the G2 checkpoint in viable conditions depends on p53. Our results suggest that integrating the GRK2/PI3K/AKT axis with non-canonical functions of p53 might confer a survival advantage to tumor cells.

molecular biology↗