Laboratoire de Spectrométrie de Masse Protéomique (LSMP)

Publications

Année de publication : 2021

Alena Ivashenka, Christian Wunder, Valerie Chambon, Roger Sandhoff, Richard Jennemann, Estelle Dransart, Katrina Podsypanina, Bérangère Lombard, Damarys Loew, Christophe Lamaze, Francoise Poirier, Hermann-Josef Gröne, Ludger Johannes, Massiullah Shafaq-Zadah (2021 Feb 10)

Glycolipid-dependent and lectin-driven transcytosis in mouse enterocytes.

Communications biology : 173 : DOI : 10.1038/s42003-021-01693-2 En savoir plus
Résumé

Glycoproteins and glycolipids at the plasma membrane contribute to a range of functions from growth factor signaling to cell adhesion and migration. Glycoconjugates undergo endocytic trafficking. According to the glycolipid-lectin (GL-Lect) hypothesis, the construction of tubular endocytic pits is driven in a glycosphingolipid-dependent manner by sugar-binding proteins of the galectin family. Here, we provide evidence for a function of the GL-Lect mechanism in transcytosis across enterocytes in the mouse intestine. We show that galectin-3 (Gal3) and its newly identified binding partner lactotransferrin are transported in a glycosphingolipid-dependent manner from the apical to the basolateral membrane. Transcytosis of lactotransferrin is perturbed in Gal3 knockout mice and can be rescued by exogenous Gal3. Inside enterocytes, Gal3 is localized to hallmark structures of the GL-Lect mechanism, termed clathrin-independent carriers. These data pioneer the existence of GL-Lect endocytosis in vivo and strongly suggest that polarized trafficking across the intestinal barrier relies on this mechanism.

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Xue Zhao, Achal Rastogi, Anne Flore Deton Cabanillas, Ouardia Ait Mohamed, Catherine Cantrel, Berangère Lombard, Omer Murik, Auguste Genovesio, Chris Bowler, Daniel Bouyer, Damarys Loew, Xin Lin, Alaguraj Veluchamy, Fabio Rocha Jimenez Vieira, Leila Tirichine (2021 Feb 3)

Genome wide natural variation of H3K27me3 selectively marks genes predicted to be important for cell differentiation in Phaeodactylum tricornutum.

The New phytologist : DOI : 10.1111/nph.17129 En savoir plus
Résumé

In multicellular organisms, Polycomb Repressive Complex2 (PRC2) is known to deposit tri-methylation of lysine 27 of histone H3 (H3K27me3) to establish and maintain gene silencing, critical for developmentally regulated processes. The PRC2 complex is absent in both widely studied model yeasts, which initially suggested that PRC2 arose with the emergence of multicellularity. However, its discovery in several unicellular species including microalgae questions its role in unicellular eukaryotes. Here, we use Phaeodactylum tricornutum enhancer of zeste E(z) knockouts and show that P. tricornutum E(z) is responsible for di- and tri-methylation of lysine 27 of histone H3. H3K27me3 depletion abolishes cell morphology in P. tricornutum providing evidence for its role in cell differentiation. Genome-wide profiling of H3K27me3 in fusiform and triradiate cells further revealed genes that may specify cell identity. These results suggest a role for PRC2 and its associated mark in cell differentiation in unicellular species, and highlight their ancestral function in a broader evolutionary context than currently is appreciated.

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Simon Bourdareau, Leila Tirichine, Bérangère Lombard, Damarys Loew, Delphine Scornet, Yue Wu, Susana M Coelho, J Mark Cock (2021 Jan 5)

Histone modifications during the life cycle of the brown alga Ectocarpus.

Genome biology : 12 : DOI : 10.1186/s13059-020-02216-8 En savoir plus
Résumé

Brown algae evolved complex multicellularity independently of the animal and land plant lineages and are the third most developmentally complex phylogenetic group on the planet. An understanding of developmental processes in this group is expected to provide important insights into the evolutionary events necessary for the emergence of complex multicellularity. Here, we focus on mechanisms of epigenetic regulation involving post-translational modifications of histone proteins.

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Année de publication : 2020

Francesca Castoldi, Juliette Humeau, Isabelle Martins, Sylvie Lachkar, Damarys Loew, Florent Dingli, Sylvère Durand, David Enot, Noëlie Bossut, Alexis Chery, Fanny Aprahamian, Yohann Demont, Paule Opolon, Nicolas Signolle, Allan Sauvat, Michaela Semeraro, Lucillia Bezu, Elisa Elena Baracco, Erika Vacchelli, Jonathan G Pol, Sarah Lévesque, Norma Bloy, Valentina Sica, Maria Chiara Maiuri, Guido Kroemer, Federico Pietrocola (2020 Dec 10)

Autophagy-mediated metabolic effects of aspirin.

Cell death discovery : 129 : DOI : 10.1038/s41420-020-00365-0 En savoir plus
Résumé

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b or Bcln1) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.

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Jessica M Bryant, Sebastian Baumgarten, Florent Dingli, Damarys Loew, Ameya Sinha, Aurélie Claës, Peter R Preiser, Peter C Dedon, Artur Scherf (2020 Aug 21)

Exploring the virulence gene interactome with CRISPR/dCas9 in the human malaria parasite.

Molecular systems biology : e9569 : DOI : 10.15252/msb.20209569 En savoir plus
Résumé

Mutually exclusive expression of the var multigene family is key to immune evasion and pathogenesis in Plasmodium falciparum, but few factors have been shown to play a direct role. We adapted a CRISPR-based proteomics approach to identify novel factors associated with var genes in their natural chromatin context. Catalytically inactive Cas9 (« dCas9 ») was targeted to var gene regulatory elements, immunoprecipitated, and analyzed with mass spectrometry. Known and novel factors were enriched including structural proteins, DNA helicases, and chromatin remodelers. Functional characterization of PfISWI, an evolutionarily divergent putative chromatin remodeler enriched at the var gene promoter, revealed a role in transcriptional activation. Proteomics of PfISWI identified several proteins enriched at the var gene promoter such as acetyl-CoA synthetase, a putative MORC protein, and an ApiAP2 transcription factor. These findings validate the CRISPR/dCas9 proteomics method and define a new var gene-associated chromatin complex. This study establishes a tool for targeted chromatin purification of unaltered genomic loci and identifies novel chromatin-associated factors potentially involved in transcriptional control and/or chromatin organization of virulence genes in the human malaria parasite.

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Anne Nehlig, Cynthia Seiler, Yulia Steblyanko, Florent Dingli, Guillaume Arras, Damarys Loew, Julie Welburn, Claude Prigent, Marin Barisic, Clara Nahmias (2020 Aug 14)

Reciprocal regulation of Aurora kinase A and ATIP3 in the control of metaphase spindle length.

Cellular and molecular life sciences : CMLS : DOI : 10.1007/s00018-020-03614-8 En savoir plus
Résumé

Maintaining the integrity of the mitotic spindle in metaphase is essential to ensure normal cell division. We show here that depletion of microtubule-associated protein ATIP3 reduces metaphase spindle length. Mass spectrometry analyses identified the microtubule minus-end depolymerizing kinesin Kif2A as an ATIP3 binding protein. We show that ATIP3 controls metaphase spindle length by interacting with Kif2A and its partner Dda3 in an Aurora kinase A-dependent manner. In the absence of ATIP3, Kif2A and Dda3 accumulate at spindle poles, which is consistent with reduced poleward microtubule flux and shortening of the spindle. ATIP3 silencing also limits Aurora A localization to the poles. Transfection of GFP-Aurora A, but not kinase-dead mutant, rescues the phenotype, indicating that ATIP3 maintains Aurora A activity on the poles to control Kif2A targeting and spindle size. Collectively, these data emphasize the pivotal role of Aurora kinase A and its mutual regulation with ATIP3 in controlling spindle length.

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Anna Zagryazhskaya-Masson, Pedro Monteiro, Anne-Sophie Macé, Alessia Castagnino, Robin Ferrari, Elvira Infante, Aléria Duperray-Susini, Florent Dingli, Arpad Lanyi, Damarys Loew, Elisabeth Génot, Philippe Chavrier (2020 Jul 17)

Intersection of TKS5 and FGD1/CDC42 signaling cascades directs the formation of invadopodia.

The Journal of cell biology : DOI : e201910132 En savoir plus
Résumé

Tumor cells exposed to a physiological matrix of type I collagen fibers form elongated collagenolytic invadopodia, which differ from dotty-like invadopodia forming on the gelatin substratum model. The related scaffold proteins, TKS5 and TKS4, are key components of the mechanism of invadopodia assembly. The molecular events through which TKS proteins direct collagenolytic invadopodia formation are poorly defined. Using coimmunoprecipitation experiments, identification of bound proteins by mass spectrometry, and in vitro pull-down experiments, we found an interaction between TKS5 and FGD1, a guanine nucleotide exchange factor for the Rho-GTPase CDC42, which is known for its role in the assembly of invadopodial actin core structure. A novel cell polarity network is uncovered comprising TKS5, FGD1, and CDC42, directing invadopodia formation and the polarization of MT1-MMP recycling compartments, required for invadopodia activity and invasion in a 3D collagen matrix. Additionally, our data unveil distinct signaling pathways involved in collagenolytic invadopodia formation downstream of TKS4 or TKS5 in breast cancer cells.

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Gilles Moulay, Jeanne Lainé, Mégane Lemaître, Masayuki Nakamori, Ichizo Nishino, Ghislaine Caillol, Kamel Mamchaoui, Laura Julien, Florent Dingli, Damarys Loew, Marc Bitoun, Christophe Leterrier, Denis Furling, Stéphane Vassilopoulos (2020 Jul 10)

Alternative splicing of clathrin heavy chain contributes to the switch from coated pits to plaques.

The Journal of cell biology : DOI : e201912061 En savoir plus
Résumé

Clathrin function directly derives from its coat structure, and while endocytosis is mediated by clathrin-coated pits, large plaques contribute to cell adhesion. Here, we show that the alternative splicing of a single exon of the clathrin heavy chain gene (CLTC exon 31) helps determine the clathrin coat organization. Direct genetic control was demonstrated by forced CLTC exon 31 skipping in muscle cells that reverses the plasma membrane content from clathrin plaques to pits and by promoting exon inclusion that stimulated flat plaque assembly. Interestingly, mis-splicing of CLTC exon 31 found in the severe congenital form of myotonic dystrophy was associated with reduced plaques in patient myotubes. Moreover, forced exclusion of this exon in WT mice muscle induced structural disorganization and reduced force, highlighting the contribution of this splicing event for the maintenance of tissue homeostasis. This genetic control on clathrin assembly should influence the way we consider how plasticity in clathrin-coated structures is involved in muscle development and maintenance.

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Sebastian M Waszak, Giles W Robinson, Brian L Gudenas, Kyle S Smith, Antoine Forget, Marija Kojic, Jesus Garcia-Lopez, Jennifer Hadley, Kayla V Hamilton, Emilie Indersie, Ivo Buchhalter, Jules Kerssemakers, Natalie Jäger, Tanvi Sharma, Tobias Rausch, Marcel Kool, Dominik Sturm, David T W Jones, Aksana Vasilyeva, Ruth G Tatevossian, Geoffrey Neale, Bérangère Lombard, Damarys Loew, Joy Nakitandwe, Michael Rusch, Daniel C Bowers, Anne Bendel, Sonia Partap, Murali Chintagumpala, John Crawford, Nicholas G Gottardo, Amy Smith, Christelle Dufour, Stefan Rutkowski, Tone Eggen, Finn Wesenberg, Kristina Kjaerheim, Maria Feychting, Birgitta Lannering, Joachim Schüz, Christoffer Johansen, Tina V Andersen, Martin Röösli, Claudia E Kuehni, Michael Grotzer, Marc Remke, Stéphanie Puget, Kristian W Pajtler, Till Milde, Olaf Witt, Marina Ryzhova, Andrey Korshunov, Brent A Orr, David W Ellison, Laurence Brugieres, Peter Lichter, Kim E Nichols, Amar Gajjar, Brandon J Wainwright, Olivier Ayrault, Jan O Korbel, Paul A Northcott, Stefan M Pfister (2020 Apr 17)

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Nature : 396-401 : DOI : 10.1038/s41586-020-2164-5 En savoir plus
Résumé

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB) ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U) position. Tumours from patients with ELP1-associated MB were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

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Bahia Bekhouche, Aurore Tourville, Yamini Ravichandran, Rachida Tacine, Laurence Abrami, Michael Dussiot, Andrea Khau-Dancasius, Olivia Boccara, Meriem Khirat, Marianne Mangeney, Florent Dingli, Damarys Loew, Batiste Boëda, Pénélope Jordan, Thierry Jo Molina, Nathalia Bellon, Sylvie Fraitag, Smail Hadj-Rabia, Stéphane Blanche, Anne Puel, Sandrine Etienne-Manneville, F Gisou van der Goot, Jacqueline Cherfils, Olivier Hermine, Jean-Laurent Casanova, Christine Bodemer, Asma Smahi, Jérôme Delon (2020 Apr 14)

A toxic palmitoylation of Cdc42 enhances NF-κB signaling and drives a severe autoinflammatory syndrome.

The Journal of allergy and clinical immunology : 1201-1204.e8 : DOI : S0091-6749(20)30426-7 En savoir plus
Résumé

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David Sitbon, Ekaterina Boyarchuk, Florent Dingli, Damarys Loew, Geneviève Almouzni (2020 Mar 11)

Histone variant H3.3 residue S31 is essential for Xenopus gastrulation regardless of the deposition pathway.

Nature communications : 1256 : DOI : 10.1038/s41467-020-15084-4 En savoir plus
Résumé

Vertebrates exhibit specific requirements for replicative H3 and non-replicative H3.3 variants during development. To disentangle whether this involves distinct modes of deposition or unique functions once incorporated into chromatin, we combined studies in Xenopus early development with chromatin assays. Here we investigate the extent to which H3.3 mutated at residues that differ from H3.2 rescue developmental defects caused by H3.3 depletion. Regardless of the deposition pathway, only variants at residue 31-a serine that can become phosphorylated-failed to rescue endogenous H3.3 depletion. Although an alanine substitution fails to rescue H3.3 depletion, a phospho-mimic aspartate residue at position 31 rescues H3.3 function. To explore mechanisms involving H3.3 S31 phosphorylation, we identified factors attracted or repulsed by the presence of aspartate at position 31, along with modifications on neighboring residues. We propose that serine 31-phosphorylated H3.3 acts as a signaling module that stimulates the acetylation of K27, providing a chromatin state permissive to the embryonic development program.

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Johanne Poisson, Marion Tanguy, Hortense Davy, Fatoumata Camara, Marie-Belle El Mdawar, Marouane Kheloufi, Tracy Dagher, Cécile Devue, Juliette Lasselin, Aurélie Plessier, Salma Merchant, Olivier Blanc-Brude, Michèle Souyri, Nathalie Mougenot, Florent Dingli, Damarys Loew, Stephane N Hatem, Chloé James, Jean-Luc Villeval, Chantal M Boulanger, Pierre-Emmanuel Rautou (2020 Feb 12)

Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm.

The Journal of clinical investigation : 2630-2643 : DOI : 10.1172/JCI124566 En savoir plus
Résumé

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

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Nuria Cortes-Silva, Jonathan Ulmer, Takashi Kiuchi, Emily Hsieh, Gaetan Cornilleau, Ilham Ladid, Florent Dingli, Damarys Loew, Susumu Katsuma, Ines A Drinnenberg (2020 Feb 8)

CenH3-Independent Kinetochore Assembly in Lepidoptera Requires CCAN, Including CENP-T.

Current biology : CB : 561-572.e10 : DOI : S0960-9822(19)31609-4 En savoir plus
Résumé

Accurate chromosome segregation requires assembly of the multiprotein kinetochore complex at centromeres. In most eukaryotes, kinetochore assembly is primed by the histone H3 variant CenH3 (also called CENP-A), which physically interacts with components of the inner kinetochore constitutive centromere-associated network (CCAN). Unexpectedly, regarding its critical function, previous work identified that select eukaryotic lineages, including several insects, have lost CenH3 while having retained homologs of the CCAN. These findings imply alternative CCAN assembly pathways in these organisms that function in CenH3-independent manners. Here we study the composition and assembly of CenH3-deficient kinetochores of Lepidoptera (butterflies and moths). We show that lepidopteran kinetochores consist of previously identified CCAN homologs as well as additional components, including a divergent CENP-T homolog, that are required for accurate mitotic progression. Our study focuses on CENP-T, which we found to be sufficient to recruit the Mis12 and Ndc80 outer kinetochore complexes. In addition, CRISPR-mediated gene editing in Bombyx mori establishes an essential function of CENP-T in vivo. Finally, the retention of CENP-T and additional CCAN homologs in other independently derived CenH3-deficient insects indicates a conserved mechanism of kinetochore assembly between these lineages. Our study provides the first functional insights into CCAN-based kinetochore assembly pathways that function independently of CenH3, contributing to the emerging picture of an unexpected plasticity to build a kinetochore.

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Giorgia Barucci, Eric Cornes, Meetali Singh, Blaise Li, Martino Ugolini, Aleksei Samolygo, Celine Didier, Florent Dingli, Damarys Loew, Piergiuseppe Quarato, Germano Cecere (2020 Feb 5)

Small-RNA-mediated transgenerational silencing of histone genes impairs fertility in piRNA mutants.

Nature cell biology : 235-245 : DOI : 10.1038/s41556-020-0462-7 En savoir plus
Résumé

PIWI-interacting RNAs (piRNAs) promote fertility in many animals. However, whether this is due to their conserved role in repressing repetitive elements (REs) remains unclear. Here, we show that the progressive loss of fertility in Caenorhabditis elegans lacking piRNAs is not caused by derepression of REs or other piRNA targets but, rather, is mediated by epigenetic silencing of all of the replicative histone genes. In the absence of piRNAs, downstream components of the piRNA pathway relocalize from germ granules and piRNA targets to histone mRNAs to synthesize antisense small RNAs (sRNAs) and induce transgenerational silencing. Removal of the downstream components of the piRNA pathway restores histone mRNA expression and fertility in piRNA mutants, and the inheritance of histone sRNAs in wild-type worms adversely affects their fertility for multiple generations. We conclude that sRNA-mediated silencing of histone genes impairs the fertility of piRNA mutants and may serve to maintain piRNAs across evolution.

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Année de publication : 2019

Despina Smirlis, Florent Dingli, Pascale Pescher, Eric Prina, Damarys Loew, Najma Rachidi, Gerald F Späth (2019 Dec 18)

SILAC-based quantitative proteomics reveals pleiotropic, phenotypic modulation in primary murine macrophages infected with the protozoan pathogen Leishmania donovani.

Journal of proteomics : 103617 : DOI : S1874-3919(19)30389-6 En savoir plus
Résumé

Leishmaniases are major vector-borne tropical diseases responsible for great human morbidity and mortality, caused by protozoan, trypanosomatid parasites of the genus Leishmania. In the mammalian host, parasites survive and multiply within mononuclear phagocytes, especially macrophages. However, the underlying mechanisms by which Leishmania spp. affect their host are not fully understood. Herein, proteomic alterations of primary, bone marrow-derived BALB/c macrophages are documented after 72 h of infection with Leishmania donovani insect-stage promastigotes, applying a SILAC-based, quantitative proteomics approach. The protocol was optimised by combining strong anion exchange and gel electrophoresis fractionation that displayed similar depth of analysis (combined total of 6189 mouse proteins). Our analyses revealed 86 differentially modulated proteins (35 showing increased and 51 decreased abundance) in response to Leishmania donovani infection. The proteomics results were validated by analysing the abundance of selected proteins. Intracellular Leishmania donovani infection led to changes in various host cell biological processes, including primary metabolism and catabolic process, with a significant enrichment in lysosomal organisation. Overall, our analysis establishes the first proteome of bona fide primary macrophages infected ex vivo with Leishmania donovani, revealing new mechanisms acting at the host/pathogen interface. SIGNIFICANCE: Little is known on proteome changes that occur in primary macrophages after Leishmania donovani infection. This study describes a SILAC-based quantitative proteomics approach to characterise changes of bone marrow-derived macrophages infected with L. donovani promastigotes for 72 h. With the application of SILAC and the use of SAX and GEL fractionation methods, we have tested new routes for proteome quantification of primary macrophages. The protocols developed here can be applicable to other diseases and pathologies. Moreover, this study sheds important new light on the « proteomic reprogramming » of infected macrophages in response to L. donovani promastigotes that affects primary metabolism, cellular catabolic processes, and lysosomal/vacuole organisation. Thus, our study reveals key molecules and processes that act at the host/pathogen interface that may inform on new immuno- or chemotherapeutic interventions to combat leishmaniasis.

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