Biology subjects

Demangel, C.

Publications and source records attributed to Demangel, C..

6 recordsLinked to original sources

bioRxiv2026

Targeting Sec61 to Silence Pathogenic Light-Chain Production in AL Amyloidosis

Unstable immunoglobulin light chains (LCs) secreted by clonal plasma cells drive organ damage in AL amyloidosis, yet no therapy exist to directly suppress their biosynthesis. Here, we targeted the Sec61 translocon to block LC biogenesis. In patient-derived plasma cells, the Sec61 blocker mycolactone redirected nascent LCs to proteasomal degradation, inducing proteotoxic stress that synergized with bortezomib. In vivo, this combination reduced plasma-cell engraftment and LC secretion but caused toxicity, underscoring the need for Sec61 client selectivity. Proteomic profiling of a model patient-derived plasma cell line treated with the synthetic Sec61 inhibitors A317 and A347 revealed intermediate- and narrow-spectrum client selectivity, respectively, while retaining activity against the LC. However, unlike A317, the more selective A347 failed to inhibit diverse amyloidogenic LCs in a signal-peptide reporter assay. In primary plasma cells from an AL cohort, A317 consistently reduced pathogenic LC production while sparing matched non-malignant bone marrow cells. Together, these findings establish Sec61 as a therapeutic target in AL amyloidosis and identify the need to balance client selectivity with coverage of diverse amyloidogenic LC signal peptides.

cell biology↗

bioRxiv2026

Defensive lipid droplets are PUFA reservoirs driving bacterial clearance and inflammation

Lipid droplets (LDs) rapidly form in infected cells to participate in the defence against microbes. Here, we investigate the involvement of LD lipids in these immune responses. Comparative shotgun and targeted lipidomics demonstrate that in vivo host LDs accumulate polyunsaturated fatty acids (PUFAs). PUFAs arrive at cells from the bloodstream to be further metabolised into complex PUFAs accrued by LD-triglycerides and -phospholipids. Host lipid metabolism is transcriptionally controlled by rapid, transient, and intricate immune programs initiated by pathogen-associated molecular patterns and relayed by cytokines such as interferons (type I and II), interleukins (IL-1{beta}), and tumour necrosis factor. When this lipid and signalling environment is reproduced in cultured macrophages, newly formed LDs accumulate defensive proteins, coordinate the synthesis of complex PUFAs, and become PUFA reservoirs and suppliers. Among LD-PUFAs, the {omega}-6 arachidonic acid is the most actively metabolised during the initial phases of innate immunity. Released from LDs by adipose triglyceride lipase, arachidonic acid is used by macrophages for prostaglandin synthesis, bacterial phagocytosis, and elimination of microbes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/711356v2_ufig1.gif" ALT="Figure 1"> View larger version (107K): org.highwire.dtl.DTLVardef@14d65eorg.highwire.dtl.DTLVardef@5ecc1org.highwire.dtl.DTLVardef@fa99e5org.highwire.dtl.DTLVardef@8d9632_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

A platform for high-throughput and ultrasensitive immunopeptidomics

Mass spectrometry (MS)-based immunopeptidomics is a powerful approach for untargeted discovery of peptides presented on major histocompatibility complex (MHC) molecules, which can guide the selection of vaccine antigens and immunotherapy targets. First-generation immunopeptidomics workflows require processing of hundreds of millions of cells using lengthy, manual procedures. More recent approaches focus on increasing either sensitivity or throughput, but rarely combine both aspects. Here, we describe a semi-automated immunopeptidomics platform that combines high sensitivity with high throughput by implementing highly optimized conditions for immunoprecipitation, elution and purification of MHC class I and II peptides on a 96-well positive-pressure device. Upon analysis of 25% of the eluate from 16 million cells, our workflow identified over 13,500 MHC I and 6,000 MHC II peptides on a timsTOF SCP mass spectrometer, operating in DDA-PASEF mode. Exploring the sensitivity limits of our platform, we identified over 1,000 MHC I peptides from as few as 20,000 JY cells. Validating the platforms performance for quantitative biological discovery, we report the identification of known and novel bacterial immunopeptides from U937 macrophages infected with Listeria monocytogenes or Bacillus Calmette-Guerin (BCG). Together, our optimized immunopeptidomics platform enables robust immunopeptide detection from lower-input samples in a high-throughput fashion, enabling its use for biological applications where sample amounts are limiting.

immunology↗

bioRxiv2021

The Sec61 translocon is a therapeutic vulnerability in Multiple Myeloma

Multiple Myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance or toxicity inevitably develop. Here, we used a recently discovered inhibitor, mycolactone, to assess the interest of targeting the Sec61 translocon in MM. In human cell lines and tumors from MM patients, mycolactone triggered pro-apoptotic endoplasmic reticulum stress responses synergizing with bortezomib for induction of MM cell death, irrespective of their resistance to proteasome inhibition. Notably, this synergy was selective of cancer cells and extended to B cell acute lymphoblastic leukemia. Sec61 blockade also caused collateral defects in MM secretion of immunoglobulins and expression of pro-survival interleukin (IL)-6 receptor and CD40, whose activation stimulates IL-6 production. Further, the mycolactone-bortezomib combination demonstrated superior therapeutic efficacy over single drug treatments in immunodeficient mice engrafted with MM cells, without inducing toxic side effects. Collectively, these findings establish Sec61 blockers as novel anti-MM agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis-addicted tumors.

cancer biology↗

bioRxiv2021

De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis

Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtbs capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However, upon activation macrophages produce polyunsaturated FAs (PUFAs), mammal-specific FAs mediating the generation of key immunomodulatory eicosanoids. Here, we asked whether de novo synthesis of PUFAs is modulated in Mtb-infected macrophages and benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection activates the early PUFA biosynthetic pathway for production of eicosanoids. While PUFA synthesis blockade significantly impaired the inflammatory and antimicrobial responses of infected macrophages, it had no effect on Mtb growth in vivo. Using a click-chemistry approach, we found that Mtb efficiently imports PUFAs of the {omega}6 subset via Mce1 in axenic culture, including the eicosanoid precursor arachidonic acid (AA). Notably, Mtb preferentially internalized AA over all other FAs within infected macrophages, but here Mtbs import of AA was largely Mce1-independent and correlated with elevated AA uptake by host cells. Together, these findings reveal AA as a major FA substrate for intracellular Mtb. They suggest that Mtbs hijacking of host-derived AA may counteract its stimulatory effect on anti-mycobacterial immune responses.

immunology↗

bioRxiv2019

The impact of gut microbiota on depressive-like behaviors and adult hippocampal neurogenesis requires the endocannabinoid system

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota, but causality remains yet to be established. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that the UCMS mice display phenotypic alterations -- characterized by an altered gut microbiota composition, a reduced adult hippocampal neurogenesis and a depressive-like behaviors -- which could be transferred from UCMS donors to naive recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota on adult neurogenesis and behavior in naive recipient mice were alleviated by selectively enhancing the central eCB tone or by adding arachidonic acid, a fatty acid precursor of eCB ligands, to the diet. In the gut of both UCMS donors and recipients, the microbiota composition was characterized by a relative decrease in Lactobacilli abundance, and complementation of the UCMS recipient microbiota with a strain of the Lactobacilli genus was sufficient to restore normal eCB brain levels, hippocampal neurogenesis and to alleviate depressive-like behaviors. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota dysbiosis generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

neuroscience↗