Biology subjects

Lelievre, E.

Publications and source records attributed to Lelievre, E..

3 recordsLinked to original sources

bioRxiv2025

Teleost-specific ictacalcins exhibit similar structural organization, cation-dependent activation and transcriptional regulation as human S100 proteins

S100 proteins are highly versatile calcium-binding proteins from vertebrates. Following extracellular release, they become instrumental in immune and antimicrobial defenses, initiating the inflammatory response through receptor signaling and providing direct control of bacterial invaders via nutritional immunity. While mammalian S100s have been extensively studied, very little is known about the more recently discovered S100 proteins from teleost fish, including those with no strict orthologs in mammals. Comparable functioning between both clades would allow to expand their study into the highly popular zebrafish model, particularly suited for live imaging and mechanistic exploration of immune and inflammatory processes. To fill the gap of knowledge on teleost S100s, we here provide a detailed structural and biochemical characterization of S100i1 and S100i2 from Danio rerio, two teleost-specific S100s absent in mammals. We demonstrate that they nevertheless share conserved tertiary and quaternary organization with mammalian S100s. In addition, they exhibit comparable calcium binding properties and undergo a similar calcium-dependent activation mechanism. Furthermore, they display analogous expression pattern, being enriched in tissues highly exposed to the environment like gills and skin, the latter constituting an important reservoir of S100 proteins in mammals. Finally, our results show, for the very first time, that s100i2/i2 gene expression is differentially modulated in sterile disease conditions associated with sustained inflammation or high hypoxic state. Altogether, these findings underline the strong parallelism existing between mammalian and teleost-specific S100 proteins despite their divergent evolution, opening up new avenues to explore their biology in the zebrafish model.

immunology↗

bioRxiv2023

The YARS Tyrosyl tRNA Synthetase Regulates Senescence Induction and Escape Through the Transcriptional Control of LIN9, a Member of the DREAM Complex

Senescence is a tumor suppressor mechanism triggered by oncogene expression and chemotherapy treatment. It orchestrates a definitive cessation of cell proliferation through the activation of the p53-p21 and p16-Rb pathways, coupled with the compaction of proliferative genes within heterochromatin regions. Some cancer cells have the ability to elude this proliferative arrest but the signaling pathways involved in circumventing senescence remain to be characterized. We have recently described that malignant cells capable of evading senescence have an increased expression of specific tRNAs, such as tRNA-Leu-CAA and tRNA-Tyr-GTA, alongside the activation of their corresponding tRNA ligases, namely LARS and YARS. We have previously shown that YARS promotes senescence escape by activating proliferation and cell cycle genes but its functions during this proliferative arrest remain largely unknown. In this study, we have continued to characterize the functions of YARS, describing non-canonical transcriptional functions of the ligase. Our results show that YARS is present in the nucleus of growing and senescent cells and interacts with the Trim28 transcriptional regulator. Importantly, YARS binds to the LIN9 promoter, a critical member of the Dream complex responsible for regulating cell cycle transcription. YARS facilitates the binding and the phosphorylation of the type II RNA polymerase and promotes the deposit of activating epigenetic marks on the LIN9 promoter. Consequently, during senescence escape, YARS promotes LIN9 expression and both proteins are necessary to induce the proliferation of emergent cells. These results underscore the unconventional transcriptional functions of YARS in promoting senescence escape by activating LIN9 and likely influencing the functions of the Dream complex.

cancer biology↗

bioRxiv2021

Endoglin deficiency elicits hypoxia-driven congestive heart failure in zebrafish.

Hereditary hemorrhagic Telangiectasia (HHT) is a rare genetic disease relying on mutations affecting components of Bone Morphogenetic Protein and Transforming Growth Factor-{beta} (BMP/TGF-{beta}) signaling pathway in endothelial cells. This disorder is characterized by arterio-venous malformations prone to rupture. and ensuing hemorrhages are responsible for iron deficiency anemia. Along with Activin receptor-like kinase ALK1, Endoglin is involved in the vast majority of HHT cases. In this report, we characterized zebrafish endoglin locus and demonstrated that it produces two phylogenetically conserved protein isoforms using a distinctive alternative splicing mechanism. Functional analysis of a Crispr/Cas9 zebrafish Endoglin mutant revealed that Endoglin deficiency results in massive death during the course from juvenile stage to adulthood. Endoglin deficient fish develop a cardiomegaly resulting in heart failure and hypochromic anemia which both stem from chronic hypoxia. Histological analysis and confocal imaging evidenced structural alterations of the developing gill and its underlying vascular network that tally with hypoxia. Finally, phenylhydrazine treatment demonstrated that lowering hematocrit/blood viscosity alleviates heart failure and enhances survival of Endoglin deficient fish. Altogether, our data indicate that Endoglin is crucial for gill vascular development and that further studies using zebrafish in general and this endoglin mutant in particular will provide crucial hints regarding the molecular and cellular events altered in HHT for the development of new therapeutic strategies. Summary StatementEndoglin deficiency in zebrafish recapitulates critical aspects of Hereditary Hemorrhagic Telangiectasia (HHT) and will thus constitute a valuable model in large scale screens for HHT-active drugs.

developmental biology↗