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1. Acylation of glycerolipids in mycobacteria

Author

Shiva Kumar Angala, Ana Carreras-Gonzalez, Emilie Huc-Claustre, Itxaso Anso, Devinder Kaur, Victoria Jones, Zuzana Palčeková, Juan M. Belardinelli, Célia de Sousa-d’Auria, Libin Shi, Nawel Slama, Christine Houssin, Annaïk Quémard, Michael McNeil, Marcelo E. Guerin, and Mary Jackson

Subjects
Science
Abstract

Abstract We report on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria, a classical one wherein the acylation of the sn-1 position of glycerol-3-phosphate (G3P) precedes that of sn-2 and another wherein acylations proceed in the reverse order. Two unique acyltransferases, PlsM and PlsB2, participate in both pathways and hold the key to the unusual positional distribution of acyl chains typifying mycobacterial glycerolipids wherein unsaturated substituents principally esterify position sn-1 and palmitoyl principally occupies position sn-2. While PlsM selectively transfers a palmitoyl chain to the sn-2 position of G3P and sn-1-lysophosphatidic acid (LPA), PlsB2 preferentially transfers a stearoyl or oleoyl chain to the sn-1 position of G3P and an oleyl chain to sn-2-LPA. PlsM is the first example of an sn-2 G3P acyltransferase outside the plant kingdom and PlsB2 the first example of a 2-acyl-G3P acyltransferase. Both enzymes are unique in their ability to catalyze acyl transfer to both G3P and LPA.

Published
2023
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2. Sortase A-Cleavable CD1d Identifies Sphingomyelins as Major Class of CD1d-Associated Lipids

Author

Maren Rudolph, Yuting Wang, Theresa Simolka, Emilie Huc-Claustre, Lingyun Dai, Gijsbert Grotenbreg, Gurdyal Singh Besra, Anna Shevchenko, Andrej Shevchenko, and Sebastian Zeissig

Subjects
CD1d, NKT cell, Sortase A, shotgun lipidomics, sphingomyelin, Immunologic diseases. Allergy, RC581-607
Abstract

CD1d is an atypical MHC class I molecule which binds endogenous and exogenous lipids and can activate natural killer T (NKT) cells through the presentation of lipid antigens. CD1d surveys different cellular compartments including the secretory and the endolysosomal pathway and broadly binds lipids through its two hydrophobic pockets. Purification of the transmembrane protein CD1d for the analysis of bound lipids is technically challenging as the use of detergents releases CD1d-bound lipids. To address these challenges, we have developed a novel approach based on Sortase A-dependent enzymatic release of CD1d at the cell surface of live mammalian cells, which allows for single step release and affinity tagging of CD1d for shotgun lipidomics. Using this system, we demonstrate that CD1d carrying the Sortase A recognition motif shows unimpaired subcellular trafficking through the secretory and endolysosomal pathway and is able to load lipids in these compartments and present them to NKT cells. Comprehensive shotgun lipidomics demonstrated that the spectrum and abundance of CD1d-associated lipids is not representative of the total cellular lipidome but rather characterized by preferential binding to long chain sphingolipids and glycerophospholipids. As such, sphingomyelin species recently identified as critical negative regulators of NKT cell activation, represented the vast majority of endogenous CD1d-associated lipids. Moreover, we observed that inhibition of endolysosomal trafficking of CD1d surprisingly did not affect the spectrum of CD1d-bound lipids, suggesting that the majority of endogenous CD1d-associated lipids load onto CD1d in the secretory rather than the endolysosomal pathway. In conclusion, we present a novel system for the analysis of CD1d-bound lipids in mammalian cells and provide new insight into the spectrum of CD1d-associated lipids, with important functional implications for NKT cell activation.

Published
2022
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3. Click-chemistry approach to study mycoloylated proteins: Evidence for PorB and PorC porins mycoloylation in Corynebacterium glutamicum.

Author

Hanane Issa, Emilie Huc-Claustre, Thamila Reddad, Nolwenn Bonadé Bottino, Maryelle Tropis, Christine Houssin, Mamadou Daffé, Nicolas Bayan, and Nathalie Dautin

Subjects
Medicine, Science
Abstract

Protein mycoloylation is a recently identified, new form of protein acylation. This post-translational modification consists in the covalent attachment of mycolic acids residues to serine. Mycolic acids are long chain, α-branched, β-hydroxylated fatty acids that are exclusively found in the cell envelope of Corynebacteriales, a bacterial order that includes important genera such as Mycobacterium, Nocardia or Corynebacterium. So far, only 3 mycoloylated proteins have been identified: PorA, PorH and ProtX from C. glutamicum. Whereas the identity and function of ProtX is unknown, PorH and PorA associate to form a membrane channel, the activity of which is dependent upon PorA mycoloylation. However, the exact role of mycoloylation and the generality of this phenomenon are still unknown. In particular, the identity of other mycoloylated proteins, if any, needs to be determined together with establishing whether such modification occurs in Corynebacteriales genera other than Corynebacterium. Here, we tested whether a metabolic labeling and click-chemistry approach could be used to detect mycoloylated proteins. Using a fatty acid alkyne analogue, we could indeed label PorA, PorH and ProtX and determine ProtX mycoloylation site. Importantly, we also show that two other porins from C. glutamicum, PorB and PorC are mycoloylated.

Published
2017
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4. The 5,6‐epoxycholesterol metabolic pathway in breast cancer: Emergence of new pharmacological targets

Author

Mehdi Attia, Khadijetou Diallo, Emilie Huc-Claustre, Sandrine Silvente-Poirot, Marc Poirot, Regis Soules, Philippe de Medina, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Réseau National Alimentation Cancer Recherche (réseau NACRe), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Poirot, Marc

Subjects
0301 basic medicine, Oxysterol, oncometabolism, Metabolite, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Breast Neoplasms, targeted therapy, cancer treatment, Targeted therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, Glucocorticoid receptor, medicine, Humans, Receptor, Carcinogen, breast, Cell Proliferation, metabolic switch, Pharmacology, business.industry, cholesterol, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Metabolic pathway, 030104 developmental biology, chemistry, Cancer research, Female, business, oxysterol, 030217 neurology & neurosurgery, Metabolic Networks and Pathways
Abstract

Metabolic pathways have emerged as cornerstones in carcinogenic deregulation providing new therapeutic strategies for cancer management. Recently, a new branch of cholesterol metabolism has been discovered involving the biochemical transformation of 5,6-epoxycholesterols (5,6-ECs). The 5,6-ECs are metabolized in breast cancers to the tumour promoter oncosterone whereas, in normal breast tissue, they are metabolized to the tumour suppressor metabolite, dendrogenin A (DDA). Blocking the mitogenic and invasive potential of oncosterone will present new opportunities for breast cancer treatment. The reactivation of DDA biosynthesis, or its use as a drug, represents promising therapeutic approaches such as DDA-deficiency complementation, activation of breast cancer cell re-differentiation and breast cancer chemoprevention. This review presents current knowledge of the 5,6-EC metabolic pathway in breast cancer, focusing on the 5,6-EC metabolic enzymes ChEH and HSD11B2 and on 5,6-EC metabolite targets, the oxysterol receptor (LXRβ) and the glucocorticoid receptor. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Published
2021

5. The 5,6-epoxycholesterol metabolic pathway in cancer: emergence of new pharmacological targets

Author

Emilie Huc-Claustre, Philippe de Medina, Khadijetou Diallo, Regis Soules, Mehdi Attia, Marc Poirot, Sandrine Silvente-Poirot, Poirot, Marc, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Drug, media_common.quotation_subject, Metabolite, [SDV]Life Sciences [q-bio], Cell, Biology, METABOLISM, law.invention, chemistry.chemical_compound, CANCER AND CARCINOGENESIS, Biosynthesis, law, medicine, NUCLEAR HORMONE RECEPTORS, Carcinogen, media_common, STEROIDS, Cancer, medicine.disease, 3. Good health, BIOCHEMICAL PHARMACOLOGY, [SDV] Life Sciences [q-bio], Metabolic pathway, medicine.anatomical_structure, chemistry, METASTASIS, Cancer research, Suppressor, CANCER PHARMACOLOGY, LIPIDS
Abstract

International audience; Metabolic pathways have emerged as cornerstones in carcinogenic deregulation providing new therapeutic strategies for cancermanagement. This is illustrated by the recent discovery of a cholesterol metabolic branch involving the biochemical transformation of 5,6-epoxycholesterol (5,6-ECs). 5,6-ECs have been shown to be differentially metabolized in breast cancers (BC)compared to normal breast tissue. 5,6-ECs are metabolized into the tumour promoter oncosterone in BC, while they aretransformed into the tumour suppressor metabolite dendrogenin A (DDA) in normal breast tissue. Blocking oncosterone’smitogenic and invasive potential will represent new opportunities for BC treatment. The reactivation of DDA biosynthesis, orits use as a drug, represents promising therapeutic approaches such as DDA-deficiency complementation, activation of BC cellre-differentiation and BC chemoprevention. This review presents current knowledge as to the 5,6-EC metabolic pathway in BCfocusing on the 5,6-EC metabolic enzymes ChEH and HSD11B2, and on 5,6-EC metabolite targets LXRβ and GR.

Published
2020

6. A fast UPLC–HILIC method for an accurate quantification of dendrogenin A in human tissues

Author

Regis Soules, Etienne Chatelut, Fabien Audouard-Combe, Marc Poirot, Ben Allal, Arnaud Rives, Sandrine Silvente-Poirot, Camille Franchet, Philippe de Medina, Emilie Huc-Claustre, Florence Dalenc, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe Labellisée par la Ligue Nationale contre le Cancer, LNCC, Waters S.A.S. [Saint-Quentin En Yvelines, France], Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius-Regaud (IUCO Toulouse), Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), M. Poirot and S. Silvente-Poirot's team was funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Toulouse III, the Institut National du Cancer (INCA, PRTKK15-118, PLBIO18-130), the Fondation Toulouse Cancer Santé (2017CS065), and the associations 'Céline' and 'Flo'., Equipe labellisée Ligue contre le Cancer, Affichem [Toulouse, France], Dendrogenix [Liège, Belgium], Institut Claudius Regaud, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Poirot, Marc, CRLCC Institut Claudius Regaud, Pôle Institut Universitaire du Cancer - Oncopole [CHU Toulouse] (Pôle IUC - Oncopole), CHU Toulouse [Toulouse]-Oncopole de Toulouse, Service d'Anatomo-Pathologie [CHU Toulouse], Centre Hospitalier Régional Universitaire de Toulouse (CHRU Toulouse), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Endocrinology, Diabetes and Metabolism, Metabolite, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Breast Neoplasms, UPLC-MS, Mass spectrometry, Biochemistry, High-performance liquid chromatography, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Oxysterol, In vivo, Quantification, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein precipitation, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Breast, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Chromatography, Hydrophilic interaction chromatography, Method development, Imidazoles, Cell Biology, In vitro, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], 030104 developmental biology, Cholesterol, chemistry, Steroidal alkaloid, Dendrogenin B, 030220 oncology & carcinogenesis, Cancer cell, Dendrogenin A, Molecular Medicine, Female, Cholestanols, Chromatography, Liquid
Abstract

International audience; Dendrogenin A (DDA) is a newly-discovered steroidal alkaloid, which remains to date the first ever found in mammals. DDA is a cholesterol metabolites that induces cancer cell differentiation and death in vitro and in vivo, and thus behave like a tumor suppressor metabolite. Preliminary studies performed on 10 patients with estrogen receptor positive breast cancers (ER(+)BC) showed a strong decrease in DDA levels between normal matched tissue and tumors. This suggests that a deregulation on DDA metabolism is associated with breast carcinogenesis. To further investigate DDA metabolism on large cohorts of patients we have developed an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS) procedure for the quantification of DDA in liquid and in solid tissues. This method enabled the identification of DDA analogues such as its geometric isomer C17 and dendrogenin B (C26) in human samples showing that other 5,6α-epoxycholesterol conjugation products with biogenic amines exist as endogenous metabolites . We report here the first complete method of quantification of DDA in liquid and solid tissues using hydrophilic interaction liquid chromatography (HILIC). Two different methods of extraction using either a Bligh and Dyer organic extraction or protein precipitation were successfully applied to quantify DDA in solid and liquid tissues. The protein precipitation method was the fastest. The fact that this method is automatable opens up possibilities to study DDA metabolism in large cohorts of patients.

Published
2019

7. Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor

Author

Loubna Mhamdi, Maud Voisin, Camille Franchet, Emmanuel Noguer, Léonor Chaltiel, Marc Poirot, Elodie Bacquié, Philippe Rochaix, Arnaud Mallinger, Aurélie Mougel, Thomas Filleron, Chiara Zerbinati, Vincent Cavaillès, Magali Lacroix-Triki, Julie Leignadier, Frédéric Lopez, Nizar Serhan, Sandrine Silvente-Poirot, Luigi Iuliano, Emilie Huc-Claustre, Gregory Segala, Talal Al Saati, Laetitia Ligat, Regis Soules, Michel Record, Raphaëlle Duprez-Paumier, Florence Dalenc, Philippe de Medina, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Institut Gustave Roussy (IGR), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM), Endocrinologie et communication cellulaire, Institut Louis Bugnard-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Institut Claudius Regaud, Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud, Sapienza University [Rome], CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Salvy-Córdoba, Nathalie

Subjects
0301 basic medicine, bBreast cancer, dendrogenin A, nuclear receptor, oncometabolism, therapy, multidisciplinary, Metabolite, Estrogen receptor, chemistry.chemical_compound, Glucocorticoid receptor, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Epoxide Hydrolases, Mice, Inbred BALB C, 3. Good health, Cholesterol, PNAS Plus, MCF-7 Cells, Female, medicine.drug, medicine.medical_specialty, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Biology, Cell Line, 03 medical and health sciences, breast cancer, Receptors, Glucocorticoid, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Cell Line, Tumor, medicine, Gene silencing, Animals, Humans, RNA, Messenger, MESH: 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism, Carcinogens/metabolism, Cholesterol/metabolism, Receptors, Glucocorticoid/metabolism, Cell growth, Estrogen Receptor alpha, Cancer, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, HEK293 Cells, Nuclear receptor, chemistry, Carcinogens, Cortisone
Abstract

International audience; Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

Published
2017

8. Assembling of the Mycobacterium tuberculosis Cell Wall Core

Author

Júlia Zemanová, Shiva K. Angala, Qian Gao, Mohamed Chami, Cecile Petit, Célia de Sousa-d'Auria, Qinglan Wang, Victoria Jones, Donald R. Ronning, Patrick J. Brennan, Juan Manuel Belardinelli, Anna E. Grzegorzewicz, Michael R. McNeil, Yoshimasa Ishizaki, Mary Jackson, Emilie Huc-Claustre, Katarína Mikušová, Christine Houssin, Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University [Fort Collins] (CSU), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Moléculaire des Corynébactéries et Mycobactéries (CORYNE), Département Microbiologie (Dpt Microbio), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Department of Chemistry and Biochemistry, University of Toledo, Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Institutes of Biomedical Sciences and Institute of Medical Microbiology, Fudan University, Institute of Microbial Chemistry (BIKAKEN), Kamiosaki, Shinagawa-ku, Tokyo, Center for Cellular Imaging and NanoAnalytics, Biozentrum [Basel, Suisse], University of Basel (Unibas)-University of Basel (Unibas), Colorado State University [Fort Collins] ( CSU ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Biologie Moléculaire des Corynébactéries et Mycobactéries ( CORYNE ), Département Microbiologie ( Dpt Microbio ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Comenius University in Bratislava, Mlynská dolina CH-1, 84215 Bratislava, and Biozentrum - University of Basel

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Glycobiology and Extracellular Matrices, cryo-electron microscopy, Biology, peptidoglycan, outer membrane, Galactans, Biochemistry, Microbiology, Corynebacterium glutamicum, Cell wall, Mycobacterium tuberculosis, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Arabinogalactan, Molecular Biology, Teichoic acid, [ SDV ] Life Sciences [q-bio], ligase, Cell Biology, biology.organism_classification, 3. Good health, Teichoic Acids, arabinogalactan, 030104 developmental biology, chemistry, polysaccharide, cell wall, Peptidoglycan, Cell envelope, Bacterial outer membrane
Abstract

International audience; The unique cell wall of mycobacteria is essential to their viability and the target of many clinically used anti-tuberculosis drugs and inhibitors under development. Despite intensive efforts to identify the ligase(s) responsible for the covalent attachment of the two major heteropolysaccharides of the mycobacterial cell wall, arabinogalactan (AG) and peptidoglycan (PG), the enzyme or enzymes responsible have remained elusive. We here report on the identification of the two enzymes of Mycobacterium tuberculosis, CpsA1 (Rv3267) and CpsA2 (Rv3484), responsible for this function. CpsA1 and CpsA2 belong to the widespread LytR-Cps2A-Psr (LCP) family of enzymes that has been shown to catalyze a variety of glycopolymer transfer reactions in Gram-positive bacteria, including the attachment of wall teichoic acids to PG. Although individual cpsA1 and cpsA2 knock-outs of M. tuberculosis were readily obtained, the combined inactivation of both genes appears to be lethal. In the closely related microorganism Corynebacterium glutamicum, the ortholog of cpsA1 is the only gene involved in this function, and its conditional knockdown leads to dramatic changes in the cell wall composition and morphology of the bacteria due to extensive shedding of cell wall material in the culture medium as a result of defective attachment of AG to PG. This work marks an important step in our understanding of the biogenesis of the unique cell envelope of mycobacteria and opens new opportunities for drug development.

Published
2016

9. Click-chemistry approach to study mycoloylated proteins: Evidence for PorB and PorC porins mycoloylation in Corynebacterium glutamicum

Author

Maryelle Tropis, Nicolas Bayan, Nolwenn Bonadé Bottino, Thamila Reddad, Christine Houssin, Nathalie Dautin, Emilie Huc-Claustre, Hanane Issa, Mamadou Daffé, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Moléculaire des Corynébactéries et Mycobactéries (CORYNE), Département Microbiologie (Dpt Microbio), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Cell Membranes, Corynebacterium, lcsh:Medicine, Biochemistry, Corynebacterium glutamicum, Serine, Amino Acids, lcsh:Science, Integral membrane protein, chemistry.chemical_classification, Multidisciplinary, biology, Chemistry, Organic Compounds, Fatty Acids, Lipids, Mycolic Acids, Physical Sciences, Metabolic Labeling, Cell envelope, Cellular Structures and Organelles, Plasmids, Research Article, Porins, Research and Analysis Methods, 03 medical and health sciences, Protein acylation, Bacterial Proteins, Hydroxyl Amino Acids, Integral Membrane Proteins, Molecular Biology Techniques, Molecular Biology, Bacteria, lcsh:R, Organic Chemistry, Organisms, Chemical Compounds, Fatty acid, Biology and Life Sciences, Membrane Proteins, Proteins, Corynebacteria, Cell Biology, biology.organism_classification, Outer Membrane Proteins, 030104 developmental biology, Membrane protein, Cell Labeling, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, lcsh:Q, Click Chemistry, Protein Processing, Post-Translational
Abstract

Protein mycoloylation is a recently identified, new form of protein acylation. This post-translational modification consists in the covalent attachment of mycolic acids residues to serine. Mycolic acids are long chain, α-branched, β-hydroxylated fatty acids that are exclusively found in the cell envelope of Corynebacteriales, a bacterial order that includes important genera such as Mycobacterium, Nocardia or Corynebacterium. So far, only 3 mycoloylated proteins have been identified: PorA, PorH and ProtX from C. glutamicum. Whereas the identity and function of ProtX is unknown, PorH and PorA associate to form a membrane channel, the activity of which is dependent upon PorA mycoloylation. However, the exact role of mycoloylation and the generality of this phenomenon are still unknown. In particular, the identity of other mycoloylated proteins, if any, needs to be determined together with establishing whether such modification occurs in Corynebacteriales genera other than Corynebacterium. Here, we tested whether a metabolic labeling and click-chemistry approach could be used to detect mycoloylated proteins. Using a fatty acid alkyne analogue, we could indeed label PorA, PorH and ProtX and determine ProtX mycoloylation site. Importantly, we also show that two other porins from C. glutamicum, PorB and PorC are mycoloylated.

Published
2016

10. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4

Author

Stefan Schreiber, Emilie Huc-Claustre, Britt-Sabina Petersen, Espen Melum, Michal Tomczak, Alan M. Leichtner, Michael Forster, Dascha C. Weir, Andre Franke, Sebastian Zeissig, Jon K. Laerdahl, Richard S. Blumberg, Bjoern Stade, and Stephanie K. Dougan

Subjects
Heterozygote, Adolescent, T cell, DNA Mutational Analysis, Mutation, Missense, chemical and pharmacologic phenomena, Autoimmunity, Penetrance, Biology, medicine.disease_cause, Article, Autoimmune Diseases, Young Adult, Immune system, Crohn Disease, medicine, Cytotoxic T cell, Humans, CTLA-4 Antigen, Exome, Age of Onset, Child, Exome sequencing, Cell Proliferation, Gastroenterology, Sequence Analysis, DNA, CD4 Lymphocyte Count, Pedigree, medicine.anatomical_structure, Diabetes Mellitus, Type 1, HEK293 Cells, CTLA-4, Immunology, B7-1 Antigen, Female, Protein Multimerization, Dimerization, Immunologic Memory, CD80, T-Lymphocytes, Cytotoxic
Abstract

Objective IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD. Design We performed exome sequencing in a family with Crohn’s disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed in silico and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function. Results A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in vitro and associated with an increased ratio of memory to naive T cells in vivo, consistent with impaired regulation of T cell activation. Conclusions Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.

Published
2014

11. RND transporters protect Corynebacterium glutamicum from antibiotics by assembling the outer membrane

Author

Liang Yang, Shuo Lu, Juan Manuel Belardinelli, Emilie Huc-Claustre, Victoria Jones, Mary Jackson, and Helen I. Zgurskaya

Subjects
Cell envelope, membrane transport, Microbiology, Corynebacterium glutamicum, Bacterial Proteins, Drug Resistance, Bacterial, Original Research, Genes, Essential, biology, Membrane transport protein, Membrane Transport Proteins, Proton-Motive Force, Membrane transport, biology.organism_classification, 3. Good health, Cell biology, Anti-Bacterial Agents, Culture Media, Membrane protein, Biochemistry, Genes, Bacterial, Gene Knockdown Techniques, biology.protein, resistance–nodulation–division family, Bacterial outer membrane, Biogenesis, Bacteria
Abstract

Corynebacterium–Mycobacterium–Nocardia (CMN) group are the causative agents of a broad spectrum of diseases in humans. A distinctive feature of these Gram-positive bacteria is the presence of an outer membrane of unique structure and composition. Recently, resistance–nodulation–division (RND) transporters (nicknamed MmpLs, Mycobacterial membrane protein Large) have emerged as major contributors to the biogenesis of the outer membranes in mycobacteria and as promising drug targets. In this study, we investigated the role of RND transporters in the physiology of Corynebacterium glutamicum and analyzed properties of these proteins. Our results show that in contrast to Gram-negative species, in which RND transporters actively extrude antibiotics from cells, in C. glutamicum and relatives these transporters protect cells from antibiotics by playing essential roles in the biogenesis of the low-permeability barrier of the outer membrane. Conditional C. glutamicum mutants lacking RND proteins and with the controlled expression of either NCgl2769 (CmpL1) or NCgl0228 (CmpL4) are hypersusceptible to multiple antibiotics, have growth deficiencies in minimal medium and accumulate intracellularly trehalose monocorynomycolates, free corynomycolates, and the previously uncharacterized corynomycolate-containing lipid. Our results also suggest that similar to other RND transporters, Corynebacterial membrane proteins Large (CmpLs) functions are dependent on a proton-motive force.

Published
2014

12. The cell envelope glycoconjugates of Mycobacterium tuberculosis

Author

Mary Jackson, Emilie Huc-Claustre, William H. Wheat, Juan Manuel Belardinelli, and Shiva K. Angala

Subjects
chemistry.chemical_classification, Antigenicity, Lipoarabinomannan, biology, Glycoconjugate, Cell Membrane, Mycobacterium tuberculosis, biology.organism_classification, Biochemistry, Models, Biological, Article, Microbiology, Biomarker, chemistry, Humans, Cell envelope, Molecular Biology, Glycoconjugates, Organism, Biogenesis, Bacterial Capsules, Glycoproteins
Abstract

Tuberculosis (TB) remains the second most common cause of death due to a single infectious agent. The cell envelope of Mycobacterium tuberculosis (Mtb), the causative agent of the disease in humans, is a source of unique glycoconjugates and the most distinctive feature of the biology of this organism. It is the basis of much of Mtb pathogenesis and one of the major causes of its intrinsic resistance to chemotherapeutic agents. At the same time, the unique structures of Mtb cell envelope glycoconjugates, their antigenicity and essentiality for mycobacterial growth provide opportunities for drug, vaccine, diagnostic and biomarker development, as clearly illustrated by recent advances in all of these translational aspects. This review focuses on our current understanding of the structure and biogenesis of Mtb glycoconjugates with particular emphasis on one of the most intriguing and least understood aspect of the physiology of mycobacteria: the translocation of these complex macromolecules across the different layers of the cell envelope. It further reviews the rather impressive progress made in the last 10 years in the discovery and development of novel inhibitors targeting their biogenesis.

Published
2014

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