Biology subjects

Fauvarque, M.-O.

Publications and source records attributed to Fauvarque, M.-O..

4 recordsLinked to original sources

bioRxiv2025

The Deubiquitinase USP36 Regulates Growth and Spermatogenesis Through Catalytic-Dependent and -Independent Mechanisms in Drosophila

Deubiquitinases (DUBs) form a specific class of proteases removing ubiquitin from target proteins. They are involved in the regulation of many cellular processes including cell growth and proliferation. Among them, USP36 is a key regulator of the oncogenic transcription factor c-Myc, preventing its degradation by the proteasome. These two proteins form an evolutionary conserved complex providing the opportunity to investigate USP36 mechanisms of action in vivo in a genetically tractable model such as Drosophila melanogaster. Null mutants of dUsp36 die early during larval development and exhibit severe growth defects. Strikingly, we report here that flies carrying a CRISPR/Cas9-induced catalytic mutation of dUsp36 survive to adulthood with only minor growth defects, yet males are infertile. This finding indicates that dUSP36 deubiquitinating activity is dispensable for cell growth but essential for spermatogenesis. Our results thus reveal that dUSP36 functions through both catalytic-dependent and catalytic-independent mechanisms, highlighting a dual mode of action with implications for the understanding of DUBs mechanism of action.

genetics↗

bioRxiv2025

Drug repurposing: halogenated salicylanilides inhibit USP8 catalytic activity and ACTH release by pituitary cells

Ubiquitin-specific protease 8 (USP8) has emerged as a crucial regulator of various cellular processes including membrane dynamics and receptor trafficking. Additionally, USP8 gain-of-function variants are frequently observed in Cushings disease, a severe condition characterized by a pituitary adenoma and dysregulated adrenocorticotropic hormone (ACTH) secretion. Moreover, USP8 overexpression contributes to resistance to chemotherapy in cancer. Here, we report the identification of Closantel, a halogenated salicylanilide, as a potent and reversible inhibitor of USP8 catalytic activity. We defined a screening approach in buffering condition counteracting the selection of oxidizing compounds and identified Closantel as a potent inhibitor of USP8 among a library of 2,240 FDA-approved drugs and compounds under clinical development. We demonstrated further that Closantel treatment led to a dose-dependent reduction of ACTH secretion by pituitary cells and resulted in the decrease in POMC gene expression, the precursor of ACTH, highlighting its potential therapeutic efficacy in Cushings disease. In addition to Closantel, we identified several other halogenated salicylanilides, including Niclosamide that is subjected to several clinical investigations in cancer treatment, as inhibitors of both USP8 activity and ACTH secretion by pituitary cells. Our findings underscore the repurposing potential of halogenated salicylanilides in targeting USP8-mediated cellular dysfunctions in Cushings disease and cancer.

pharmacology and toxicology↗

bioRxiv2020

The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis

Pseudomonas aeruginosa is a causative agent in nosocomial infections, notably in ventilated or cystic fibrosis patients. P. aeruginosa isolates expressing the phospholipase ExoU, an effector of the type III secretion system, are the most pathogenic in clinics. Here, using a genome-wide screen, we discovered that ExoU toxicity requires DNAJC5, a host chaperone, to exert its necrotic activity. DNAJC5 is involved in an unconventional secretory pathway for misfolded proteins involving anterograde vesicular trafficking. DNAJC5-deficient human cells or Drosophila flies knocked-down for the DNAJC5 orthologue were largely resistant to ExoU virulence. ExoU colocalized with DNAJC5-positive vesicles in the host cytoplasm. DNAJC5 mutations preventing vesicle trafficking - identified in adult neuronal ceroid lipofuscinosis, a human congenital disease - inhibited ExoU-dependent cell lysis. These results suggest that, once injected into the host cytoplasm, ExoU docks to DNAJC5-positive secretory vesicles to reach the plasma membrane, where its phospholipase activity is triggered by binding to PI(4,5)P2.

microbiology↗

bioRxiv2018

Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila

One Sentence SummaryUpon microbial infection in Drosophila, the E3-ubiquitin ligase Hyd ubiquitinylates the NF-{kappa}B co-factor Akirin for its efficient binding to the NF-{kappa}B factor Relish and subsequent activation of immune effectors genes.\n\nABSTRACTThe Drosophila IMD pathway is activated upon microbial challenge with Gramnegative bacteria to trigger the innate immune response. In order to decipher this NF-{kappa}B signaling pathway, we undertook an ex-vivo RNAi screen targeting specifically E3 ubiquitin ligases and identified the HECT E3 ubiquitin ligase Hyperplastic Discs \"Hyd\" as a new actor of the IMD pathway. We showed that Hyd targets the NF-{kappa}B cofactor of Akirin. The K63-polyubiquitination chains deposited by Hyd decorate Akirin for its efficient binding to the NF-{kappa}B transcription factor Relish. We showed that this Hyd-mediated interaction is critical to activate immune-induced genes that depend on both Relish and Akirin, but is dispensable for those that depend solely on Relish. Therefore Hyd is key in operating a NF-{kappa}B transcriptional selectivity downstream of the IMD pathway. Drosophila depleted for Hyd or Akirin failed to express the full set of immune-induced anti-microbial peptide coding genes and succumbed to immune challenges. We showed further that Ubr5, the mammalian homolog of Hyd, is also required downstream of the NF-{kappa}B pathway for the IL1{beta}-mediated IL6 activation. This study links the action of a E3-ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.

immunology↗