Biology subjects

Auberger, P.

Publications and source records attributed to Auberger, P..

5 recordsLinked to original sources

bioRxiv2025

Non-canonical caspase-8 activation by cathepsin B drives anti-inflammatory human macrophage polarization

Anti-inflammatory monocyte-derived macrophages are essential to maintain tissue homeostasis but can also contribute to disease progression, notably in cancer and fibrosis. Deciphering the signaling pathways that govern their generation could therefore unlock new therapeutic opportunities. Here we uncover a previously unrecognized, non-apoptotic function of caspase-8 in driving both monocyte-to-macrophage differentiation and anti-inflammatory macrophages polarization. We identified cathepsin B as a novel upstream activator of caspase-8 activation through a non-canonical cleavage mechanism, conferring to caspase-8 an original activity profile distinct from its apoptotic role. Disruption of this cathepsin-B-caspase-8 axis, either genetically or pharmacologically, not only impairs the generation of anti-inflammatory macrophages but also reprograms these cells towards a pro-inflammatory phenotype. Our findings position the cathepsin-B-caspase-8 axis as a critical regulatory node in macrophage fate decisions and a promising target for therapeutic reprogramming of human macrophages in cancer, inflammation and fibrotic diseases.

immunology↗

bioRxiv2025

CSF1R regulates monocyte subset differentiation and intracellular metabolism.

Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6Chigh) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6Clow) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6Clow monocytes in part by blunting differentiation of Ly6Chigh monocytes. Based upon lineage-specific deletion of GFPT1 (Glutamine-Fructose-6-Phosphate Transaminase 1), the hexosamine biosynthetic pathway (HBP) is identified as a novel regulator of CSF1R expression and monocyte subset diversity. Our findings provide new insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.

immunology↗

bioRxiv2024

Dual targeting of GPX4 and TXNRD1 triggers eradication of AML cells through induction of apoptosis and ferroptosis

MyeloDysplastic Syndromes (MDS) are a group of heterogeneous hematological disorders characterized by bone marrow failure and abnormal hematopoietic cell expansion, often progressing to acute myeloid leukemia (AML). Current treatments for AML and high-risk MDS have limited efficacy, requiring the exploration of new therapeutic approaches. Recent research highlighted the potential of inducing cell death through ferroptosis, either independently or alongside traditional chemotherapy, as promising approaches for treating MDS/AML cells. We described here two novel compounds, HA344 and #231, capable of targeting both ferroptosis and apoptosis, leading to the effective eradication of cell lines and primary blasts from MDS/AML patients, while sparing normal hematopoietic cells. RNASeq analysis identified oxidation reduction and apoptotic processes as highly significant induced pathways in two different AML cell lines. Using click-chemistry approaches coupled to mass spectrometry, we identified glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1) as the main targets of HA344 and #231 in a large panel of AML cells. Accordingly, both compounds inhibited GPX4 and TXNRD1 activity in the micromolar range and triggered GPX4 degradation. Moreover, using recombinant GPX4 carrying or not a selenium (GPX4-Se and GPX4-S), we confirmed by mass spectrometry that HA344 and #231 bind more efficiently GPX4-Se than GPX4-S. In conclusion, these compounds might represent a new pharmacological approach in the treatment of MDS and AML, offering a potential avenue for future therapies.

biochemistry↗

bioRxiv2023

MCB-613 exploits a collateral sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer through covalent inhibition of KEAP1

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR-mutant NSCLC cells.

cancer biology↗

bioRxiv2022

HSPA8 chaperone complex drives chaperone-mediated autophagy regulation in acute promyelocytic leukemia differentiation

Acute myeloid leukemia (AML) is a cancer of the hematopoietic system characterized by the hyperproliferation of undifferentiated cells of the myeloid lineage. While most of AML therapy are focusing on tumor debulking, all-trans retinoic acid (ATRA) induces differentiation in acute promeylocytic leukemia (APL) a particular subtype. Macroautophagy has been extensively investigated in the context of various cancers and is often dysregulated in AML where it can have context-dependent pro- or anti-leukemogenic effects. On the contrary, the implications of chaperone-mediated autophagy (CMA) on the pathophysiology of diseases are still being explored and its role in AML has remained elusive. To answer our questions we took advantages of human AML primary samples and databases. Furthermore, we used ATRA-sensitive (NB4) and -resistant (NB4-R1) cells to further dissect a potential function for CMA in ATRA-mediated neutrophil differentiation. NB4-R1 cells are unique in that they do respond to retinoic acid transcriptionally, but do not mature in response to retinoid signaling alone unless maturation is triggered by adding cAMP. Here, we report that CMA related mRNA transcripts are higher expressed in immature hematopoietic cells as compared to neutrophils. In line, lysosomal degradation of mCherry-KFERQ CMA reporter decreases during ATRA-induced differentiation of APL cells. On the other hand, using NB4-R1 cells we found that macroautophagy flux primed the ATRA resistant NB4-R1 cells to differentiate upon ATRA treatment, but reduced association of LAMP-2A and HSPA8 is necessary for complete neutrophil maturation. Accordingly, depletion of HSPA8 attenuated CMA activity and facilitated APL differentiation. In contrast, maintaining high CMA activity by ectopic expression of LAMP-2A impeded APL differentiation. Overall, our findings demonstrate that both normal and APL neutrophil differentiation require CMA downregulation and this pathway is predominantly dependent on HSPA8 assisted by other co-chaperones.

cancer biology↗