Biology subjects

Aubert, Y.

Publications and source records attributed to Aubert, Y..

6 recordsLinked to original sources

bioRxiv2026

A PTBP1-CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high rates of relapse and poor outcomes, especially in elderly or unfit patients, who cannot tolerate intensive chemotherapy. While the BCL2 inhibitor venetoclax has improved initial responses in this high-risk population, relapses remain nearly universal, highlighting the need for novel therapeutic strategies. Here, we identify the RNA-binding protein PTBP1 as a critical dependency in AML. PTBP1 depletion impairs leukemic growth in vitro and in vivo, and is associated with widespread splicing alterations and global disruption of protein synthesis. Integrative transcriptomic and iCLIP analyses reveal that PTBP1 orchestrates a splicing program centered on Rho GTPase signaling, with CDC42 as a key downstream effector. Mechanistically, PTBP1 loss triggers a splicing switch from CDC42-v1 to CDC42-v2, leading to reduced GTPase activity and impaired protein synthesis. Pharmacological inhibition of CDC42 selectively induces cytotoxicity in AML cells, while sparing healthy hematopoietic cells. Importantly, CDC42 inhibition markedly enhances venetoclax anti-leukemic efficacy. These findings establish PTBP1 as a critical regulator of AML cell fitness and identify a clinically actionable therapeutic combination that exploits AML dependency on PTBP1-CDC42 signaling to enhance the efficacy of venetoclax-based regimens.

cancer biology↗

bioRxiv2024

Post-transcriptional control of homeostatic B- cell signalling by HuR is required for innate B cell maintenance and function.

Innate B-1 cells constitute a self-maintained layer of defence for early detection of bacteria, clearance of apoptotic cell debris and removal of autoantigens driving autoimmunity. B-1 cells are originated from foetal tissues but, as opposed to B-2 cells, the molecular mechanisms behind their development and homeostatic maintenance remain largely unknown. Here we demonstrate that post-transcriptional regulation by the RNA binding protein HuR is essential for the homeostatic self-replenishment of innate B-1 cells, the expansion of B-1 cell clones targeting self-antigens and the production of natural autoantibodies. HuR KO B-1 cells fail to express the high levels of surface BCR, TACI and BAFFR required for tonic signalling and cell survival. Mechanistically, HuR binds to the 3UTRs of mRNAs encoding these surface receptors and of pro-survival molecules, like BCL-2 and MCL-1, promoting their translation into protein. In summary, we reveal the need of post-transcriptional regulation in BCR expression, tonic signalling and homeostatic maintenance of functional B-1 cells.

immunology↗

bioRxiv2024

Post-transcriptional regulation by TIA1 and TIAL1 controls the transcriptional program enforcing T cell quiescence.

Immune protection against new and recurrent infections relies on long-term maintenance of a highly diversified T-cell repertoire. Transcription factors cooperate to enforce T-cell metabolic quiescence and maintenance. However, less is known about the post-transcriptional networks that preserve peripheral naive T cells. Here we describe the RNA binding proteins TIA1 and TIAL1 as key promoters of CD4 and CD8 T cell quiescence. T cells deficient in TIA1 and TIAL1 undergo uncontrolled cell proliferation in the absence of cognate antigens, leading this to a premature T-cell activation, exhaustion and death. Mechanistically, TIA1 and TIAL1 control the expression of master regulatory transcription factors, FOXP1, LEF1 and TCF1, that restrain homeostatic T-cell proliferation. In summary, our study highlights a previously unrecognised dependency on post-transcriptional gene regulation by TIA1 and TIAL1 for implementing the quiescent transcriptional programs for long survival of T cells.

immunology↗

bioRxiv2021

Human Cytomegalovirus modifies placental small extracellular vesicle secretion and composition towards a proviral phenotype to enhance infection of fetal recipient cells

Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during human cytomegalovirus (hCMV) congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of hCMV infection on sEVs production, composition and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from either an ex vivo model of infected histocultures from early placenta or from the amniotic fluid of patients naturally infected by hCMV at the beginning of pregnancy. Based on these findings, we propose that placental sEVs could be key actors favoring viral dissemination to the fetal brain during hCMV congenital infection. Significance StatementHuman cytomegalovirus (hCMV) infection is a major issue during pregnancy, affecting 1% of births in western countries. Despite extensive research, the pathophysiology of this congenital infection remains unclear. Recently, increasing evidence point to the key role of placental small extracellular vesicles (sEVs) in materno-fetal communication during pregnancy. Here, we examined the impact of hCMV infection on the protein composition and function of placental sEVs. We observe that hCMV infection leads to major changes in placental sEV protein content. Functional studies show the ability of sEVs produced by placental infected cells to facilitate further infection of naive recipient fetal cells, notably human neural stem cells. Our study demonstrates that placental sEVs are key players of hCMV pathophysiology during congenital infection.

cell biology↗

bioRxiv2021

MLL4 is a critical mediator of differentiation and ferroptosis in the epidermis

The epigenetic regulator, MLL4 (KMT2D), has been described as an essential gene in both humans and mice1,2. In addition, it is one of the most commonly mutated genes in all of cancer biology3-7. Here, we identify a critical role for Mll4 in the promotion of epidermal differentiation and ferroptosis, a key mechanism of tumor suppression8,9. Mice lacking epidermal Mll4, but not the related enzyme Mll3 (Kmt2c), display features of impaired differentiation and human pre-cancerous neoplasms, including epidermal hyperplasia, atypical keratinocytes, and a loss of polarization, all of which progress with age. Mll4 deficiency profoundly alters epidermal gene expression, and uniquely rewires the expression of key genes and markers of ferroptosis (Alox12, Alox12b, Aloxe3)10. Beyond identifying a novel role for Mll4-mediated tumor suppression in the skin, our data reveal a potentially much more broad and general role for ferroptosis in the process of epidermal differentiation and skin homeostasis.

cancer biology↗

bioRxiv2021

Differential gene expression by RNA-Seq in Sigma-2 Receptor/TMEM97 knockout cells reveals its role in complement activation and SARS-CoV-2 viral uptake

Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (sigma-2R/TMEM97) interacts with the low-density lipoprotein receptor (LDLR) and facilitates the enhanced uptake of various ligands including lipoproteins and intrinsically disordered proteins. TMEM97 has been recently been shown to interact with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins, highlighting its potential involvement with viral entry into the cell. We hypothesized that sigma-2R/TMEM97 may play a role in facilitating viral uptake, and with the regulation of inflammatory and thrombotic pathways that are involved with viral infection. In this study, we identified the top differentially expressed genes upon the knockout of sigma-2R/TMEM97, and analyzed the genes involved with the inflammatory and thrombotic cascades, effects that are observed in patients infected with SARS-CoV-2. We found that the ablation of sigma-2R/TMEM97 resulted in an increase in Complement Component 4 Binding Protein (C4BP) proteins, at both the translational and transcriptional levels. We also showed that sigma-2R/TMEM97 interacts with the cellular receptor for SARS-CoV-2, the human angiotensin-converting enzyme 2 (ACE2) receptor, forming a protein complex, and that disruption of this complex results in the inhibition of viral uptake. The results of this study suggest that sigma-2R/TMEM97 may be a novel therapeutic target to inhibit SARS-CoV-2 viral uptake, as well as to decrease inflammatory and thrombotic effects through the modulation of the complement cascade.

cell biology↗