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A challenge for the development of host-targeted anti-infectives against a large spectrum of AB-like toxin-producing bacteria encompasses the identification of chemical compounds corrupting toxin transport through both endolysosomal and retrograde pathways. Here, we performed a high-throughput screening of small chemical compounds blocking active Rac1 proteasomal degradation triggered by the Cytotoxic Necrotizing Factor-1 (CNF1) toxin, followed by orthogonal screens against two AB toxins hijacking defined endolysosomal (Diphtheria toxin) or retrograde (Shiga-like toxin 1) pathways to intoxicate cells. This led to the identification of the molecule N-(3,3-diphenylpropyl)-1-propyl-4-piperidinamine, referred to as C910. This compound induces the swelling of EEA1-positive early endosomes, in absence of PIKfyve kinase inhibition, and disturbs the trafficking of CNF1 and the B-subunit of Shiga toxin along the endolysosomal or retrograde pathways, respectively. Together, we show that C910 protects cells against 8 bacterial AB toxins including large clostridial glucosylating toxins from Clostridium difficile. Of interest, C910 also reduced viral infection in vitro including influenza A virus subtype H1N1 and SARS-CoV-2. Moreover, parenteral administration of C910 to the mice resulted in its accumulation in lung tissues and reduced lethal influenza infection.
Yu Wu; Nassim Mahtal; Léa Swistak; Sara Sagadiev; Mridu Acharya; Caroline Demeret; Sylvie van der Werf; Florence Guivel-Benhassine; Olivier Schwartz; Serena Petracchini; Amel Mettouchi; Eléa Paillares; Lucie Caramelle; Pierre Couvineau; Robert Thai; Peggy Barbe; Mathilde Keck; Priscille Brodin; Arnaud Machelart; Valentin Sencio; François Trottein; Martin Sachse; Gaëtan Chicanne; Bernard Payrastre; Florian Ville; Victor Kreis; Michel-Robert Popoff; Ludger Johannes; Jean-Christophe Cintrat; Julien Barbier; Daniel Gillet; Emmanuel Lemichez. A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2. 2021, 1 .
AMA StyleYu Wu, Nassim Mahtal, Léa Swistak, Sara Sagadiev, Mridu Acharya, Caroline Demeret, Sylvie van der Werf, Florence Guivel-Benhassine, Olivier Schwartz, Serena Petracchini, Amel Mettouchi, Eléa Paillares, Lucie Caramelle, Pierre Couvineau, Robert Thai, Peggy Barbe, Mathilde Keck, Priscille Brodin, Arnaud Machelart, Valentin Sencio, François Trottein, Martin Sachse, Gaëtan Chicanne, Bernard Payrastre, Florian Ville, Victor Kreis, Michel-Robert Popoff, Ludger Johannes, Jean-Christophe Cintrat, Julien Barbier, Daniel Gillet, Emmanuel Lemichez. A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2. . 2021; ():1.
Chicago/Turabian StyleYu Wu; Nassim Mahtal; Léa Swistak; Sara Sagadiev; Mridu Acharya; Caroline Demeret; Sylvie van der Werf; Florence Guivel-Benhassine; Olivier Schwartz; Serena Petracchini; Amel Mettouchi; Eléa Paillares; Lucie Caramelle; Pierre Couvineau; Robert Thai; Peggy Barbe; Mathilde Keck; Priscille Brodin; Arnaud Machelart; Valentin Sencio; François Trottein; Martin Sachse; Gaëtan Chicanne; Bernard Payrastre; Florian Ville; Victor Kreis; Michel-Robert Popoff; Ludger Johannes; Jean-Christophe Cintrat; Julien Barbier; Daniel Gillet; Emmanuel Lemichez. 2021. "A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2." , no. : 1.
Compared to conventional antisera strategies, monoclonal antibodies (mAbs) represent an alternative and safer way to treat botulism, a fatal flaccid paralysis due to botulinum neurotoxins (BoNTs). In addition, mAbs offer the advantage to be produced in a reproducible manner. We previously identified a unique and potent mouse mAb (TA12) targeting BoNT/A1 with high affinity and neutralizing activity. In this study, we characterized the molecular basis of TA12 neutralization by combining Hydrogen/Deuterium eXchange Mass Spectrometry (HDX‐MS) with site‐directed mutagenesis and functional studies. We found that TA12 recognizes a conformational epitope located at the interface between the HCN and HCC subdomains of the BoNT/A1 receptor‐binding domain (HC). The TA12‐binding interface shares common structural features with the ciA‐C2 VHH epitope and lies on the face opposite recognized by ciA‐C2‐ and the CR1/CR2‐neutralizing mAbs. The single substitution of N1006 was sufficient to affect TA12 binding to HC confirming the position of the epitope. We further uncovered that the TA12 epitope overlaps with the BoNT/A1‐binding site for both the neuronal cell surface receptor synaptic vesicle glycoprotein 2 isoform C (SV2C) and the GT1b ganglioside. Hence, TA12 potently blocks the entry of BoNT/A1 into neurons by interfering simultaneously with the binding of SV2C and to a lower extent GT1b. Our study reveals the unique neutralization mechanism of TA12 and emphasizes on the potential of using single mAbs for the treatment of botulism type A.
Sébastien Brier; Christine Rasetti‐Escargueil; Anne Wijkhuisen; Stéphanie Simon; Maud Marechal; Emmanuel Lemichez; Michel R. Popoff. Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A. The FASEB Journal 2021, 35, e21540 .
AMA StyleSébastien Brier, Christine Rasetti‐Escargueil, Anne Wijkhuisen, Stéphanie Simon, Maud Marechal, Emmanuel Lemichez, Michel R. Popoff. Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A. The FASEB Journal. 2021; 35 (5):e21540.
Chicago/Turabian StyleSébastien Brier; Christine Rasetti‐Escargueil; Anne Wijkhuisen; Stéphanie Simon; Maud Marechal; Emmanuel Lemichez; Michel R. Popoff. 2021. "Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A." The FASEB Journal 35, no. 5: e21540.
Staphylococcus aureus is the most prevalent pathogen isolated from diabetic foot infections (DFIs). The purpose of this study was to evaluate its behavior in an in vitro model mimicking the conditions encountered in DFI. Four clinical S. aureus strains were cultivated for 16 weeks in a specific environment based on the wound-like medium biofilm model. The adaptation of isolates was evaluated as follows: by Caenorhabditis elegans model (to evaluate virulence); by quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) (to evaluate expression of the main virulence genes); and by Biofilm Ring test® (to assess the biofilm formation). After 16 weeks, the four S. aureus had adapted their metabolism, with the development of small colony variants and the loss of β-hemolysin expression. The in vivo nematode model suggested a decrease of virulence, confirmed by qRT-PCRs, showing a significant decrease of expression of the main staphylococcal virulence genes tested, notably the toxin-encoding genes. An increased expression of genes involved in adhesion and biofilm was noted. Our data based on an in vitro model confirm the impact of environment on the adaptation switch of S. aureus to prolonged stress environmental conditions. These results contribute to explore and characterize the virulence of S. aureus in chronic wounds.
Cassandra Pouget; Claude-Alexandre Gustave; Christelle Ngba-Essebe; Frédéric Laurent; Emmanuel Lemichez; Anne Tristan; Albert Sotto; Catherine Dunyach-Rémy; Jean-Philippe Lavigne. Adaptation of Staphylococcus aureus in a Medium Mimicking a Diabetic Foot Environment. Toxins 2021, 13, 230 .
AMA StyleCassandra Pouget, Claude-Alexandre Gustave, Christelle Ngba-Essebe, Frédéric Laurent, Emmanuel Lemichez, Anne Tristan, Albert Sotto, Catherine Dunyach-Rémy, Jean-Philippe Lavigne. Adaptation of Staphylococcus aureus in a Medium Mimicking a Diabetic Foot Environment. Toxins. 2021; 13 (3):230.
Chicago/Turabian StyleCassandra Pouget; Claude-Alexandre Gustave; Christelle Ngba-Essebe; Frédéric Laurent; Emmanuel Lemichez; Anne Tristan; Albert Sotto; Catherine Dunyach-Rémy; Jean-Philippe Lavigne. 2021. "Adaptation of Staphylococcus aureus in a Medium Mimicking a Diabetic Foot Environment." Toxins 13, no. 3: 230.
Metabolic studies and animal knockout models point to the critical role of polyunsaturated docosahexaenoic acid (22:6, DHA)-containing phospholipids (PLs) in physiology. Here, we study the impact of DHA-PLs on the dynamics of transendothelial cell macroapertures (TEMs) tunnels triggered by the RhoA GTPase inhibitory exotoxin C3 from Clostridium botulinum. Through lipidomic analyses, we show that primary human umbilical vein endothelial cells (HUVECs) subjected to DHA-diet undergo a 6-fold DHA-PLs enrichment in plasma membrane at the expense of monounsaturated OA-PLs. In contrast, OA-diet had almost no effect on PLs composition. Consequently, DHA treatment increases the nucleation rate of TEMs by 2-fold that we ascribe to a reduction of cell thickness. We reveal that the global transcellular area of cells remains conserved through a reduction of the width and lifetime of TEMs. Altogether, we reveal a homeostasis between plasma membrane DHA-PLs content and large-scale membrane dynamics.
Meng-Chen Tsai; Lucile Fleuriot; Sébastien Janel; David Gonzalez-Rodriguez; Camille Morel; Amel Mettouchi; Delphine Debayle; Stéphane Dallongeville; Jean-Christophe Olivo-Marin; Bruno Antonny; Frank Lafont; Emmanuel Lemichez; Hélène Barelli. Docosahexaenoic fatty acid-containing phospholipids affect plasma membrane susceptibility to disruption by bacterial toxin-induced macroapertures. 2020, 1 .
AMA StyleMeng-Chen Tsai, Lucile Fleuriot, Sébastien Janel, David Gonzalez-Rodriguez, Camille Morel, Amel Mettouchi, Delphine Debayle, Stéphane Dallongeville, Jean-Christophe Olivo-Marin, Bruno Antonny, Frank Lafont, Emmanuel Lemichez, Hélène Barelli. Docosahexaenoic fatty acid-containing phospholipids affect plasma membrane susceptibility to disruption by bacterial toxin-induced macroapertures. . 2020; ():1.
Chicago/Turabian StyleMeng-Chen Tsai; Lucile Fleuriot; Sébastien Janel; David Gonzalez-Rodriguez; Camille Morel; Amel Mettouchi; Delphine Debayle; Stéphane Dallongeville; Jean-Christophe Olivo-Marin; Bruno Antonny; Frank Lafont; Emmanuel Lemichez; Hélène Barelli. 2020. "Docosahexaenoic fatty acid-containing phospholipids affect plasma membrane susceptibility to disruption by bacterial toxin-induced macroapertures." , no. : 1.
Human botulism is a severe disease characterized by flaccid paralysis and inhibition of certain gland secretions, notably salivary secretions, caused by inhibition of neurotransmitter release. Naturally acquired botulism occurs in three main forms: food-borne botulism by ingestion of preformed botulinum neurotoxin (BoNT) in food, botulism by intestinal colonization (infant botulism and intestinal toxemia botulism in infants above one year and adults), and wound botulism. A rapid laboratory confirmation of botulism is required for the appropriate management of patients. Detection of BoNT in the patient’s sera is the most direct way to address the diagnosis of botulism. Based on previous published reports, botulinum toxemia was identified in about 70% of food-borne and wound botulism cases, and only in about 28% of infant botulism cases, in which the diagnosis is mainly confirmed from stool sample investigation. The presence of BoNT in serum depends on the BoNT amount ingested with contaminated food or produced locally in the intestine or wound, and the delay between serum sampling and disease onset. BoNT levels in patient’s sera are most frequently low, requiring a highly sensitive method of detection. Mouse bioassay is still the most used method of botulism identification from serum samples. However, in vitro methods based on BoNT endopeptidase activity with detection by mass spectrometry have been developed and depending on BoNT type, are more sensitive than the mouse bioassay. These new assays show high specificity for individual BoNT types and allow the differentiation between positive toxin sera from botulism and autoimmune neuropathy patients.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Toxemia in Human Naturally Acquired Botulism. Toxins 2020, 12, 716 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Toxemia in Human Naturally Acquired Botulism. Toxins. 2020; 12 (11):716.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2020. "Toxemia in Human Naturally Acquired Botulism." Toxins 12, no. 11: 716.
Pathogenic bacteria colonize or disseminate into cells and tissues by inducing large-scale remodeling of host membranes. The physical phenomena underpinning these massive membrane extension and deformation are poorly understood. Invasive strategies of pathogens have been recently enriched by the description of a spectacular mode of opening of large transendothelial cell macroaperture (TEM) tunnels correlated to the dissemination of EDIN-producing strains of Staphylococcus aureus via a hematogenous route or to the induction of gelatinous edema triggered by the edema toxin from Bacillus anthracis. Remarkably, these highly dynamic tunnels close rapidly after they reach a maximal size. Opening and closure of TEMs in cells lasts for hours without inducing endothelial cell death. Multidisciplinary studies have started to provide a broader perspective of both the molecular determinants controlling cytoskeleton organization at newly curved membranes generated by the opening of TEMs and the physical processes controlling the dynamics of these tunnels. Here we discuss the analogy between the opening of TEM tunnels and the physical principles of dewetting, stemming from a parallel between membrane tension and surface tension. This analogy provides a broad framework to investigate biophysical constraints in cell membrane dynamics and their diversion by certain invasive microbial agents.
David Gonzalez-Rodriguez; Camille Morel; Emmanuel Lemichez. Dewetting: From Physics to the Biology of Intoxicated Cells. Advances in Experimental Medicine and Biology 2020, 101 -115.
AMA StyleDavid Gonzalez-Rodriguez, Camille Morel, Emmanuel Lemichez. Dewetting: From Physics to the Biology of Intoxicated Cells. Advances in Experimental Medicine and Biology. 2020; ():101-115.
Chicago/Turabian StyleDavid Gonzalez-Rodriguez; Camille Morel; Emmanuel Lemichez. 2020. "Dewetting: From Physics to the Biology of Intoxicated Cells." Advances in Experimental Medicine and Biology , no. : 101-115.
Botulism is a rare but severe disease which is characterized by paralysis and inhibition of secretions. Only a few cases had been reported at the end of the 19th century in France. The disease was frequent during the second world war, and then the incidence decreased progressively. However, human botulism is still present in France with 10–25 cases every year. Food-borne botulism was the main form of botulism in France, whereas infant botulism (17 cases between 2004 and 2016) was rare, and wound and inhalational botulism were exceptional. Type B was the prevalent botulism type and was mainly due to consumption of home-made or small-scale preparations of cured ham and to a lesser extent other pork meat products. In the recent period (2000–2016), a wider diversity of botulism types from various food origin including industrial foods was reported. Severe cases of type A and F botulism as well as type E botulism were more frequent. Albeit rare, the severity of botulism justifies its continued surveillance and recommendations to food industry and consumers regarding food hygiene and preservation practices.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Human Botulism in France, 1875–2016. Toxins 2020, 12, 338 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Human Botulism in France, 1875–2016. Toxins. 2020; 12 (5):338.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2020. "Human Botulism in France, 1875–2016." Toxins 12, no. 5: 338.
Intimate interactions between the armament of pathogens and their host dictate tissue and host susceptibility to infection also forging specific pathophysiological outcomes. Studying these interactions at the molecular level has provided an invaluable source of knowledge on cellular processes, as ambitioned by the Cellular Microbiology discipline when it emerged in early 90s. Bacterial toxins act on key cell regulators or membranes to produce major diseases and therefore constitute a remarkable toolbox for dissecting basic biological processes. Here, we review selected examples of recent studies on bacterial toxins illustrating how fruitful the discipline of cellular microbiology is in shaping our understanding of eukaryote processes. This ever‐renewing discipline unveils new virulence factor biochemical activities shared by eukaryotic enzymes and hidden rules of cell proteome homeostasis, a particularly promising field to interrogate the impact of proteostasis breaching in late onset human diseases. It is integrating new concepts from the physics of soft matter to capture biomechanical determinants forging cells and tissues architecture. The success of this discipline is also grounded by the development of therapeutic tools and new strategies to treat both infectious and noncommunicable human diseases.
Emmanuel Lemichez; Michel Robert Popoff; Karla J. F. Satchell. Cellular microbiology: Bacterial toxin interference drives understanding of eukaryotic cell function. Cellular Microbiology 2020, 22, e13178 .
AMA StyleEmmanuel Lemichez, Michel Robert Popoff, Karla J. F. Satchell. Cellular microbiology: Bacterial toxin interference drives understanding of eukaryotic cell function. Cellular Microbiology. 2020; 22 (4):e13178.
Chicago/Turabian StyleEmmanuel Lemichez; Michel Robert Popoff; Karla J. F. Satchell. 2020. "Cellular microbiology: Bacterial toxin interference drives understanding of eukaryotic cell function." Cellular Microbiology 22, no. 4: e13178.
The ionophore lasalocid is widely used as a veterinary drug against coccidiosis. We found recently that lasalocid protects cells from two unrelated bacterial toxins, the cytotoxic necrotizing factor-1 (CNF1) from Escherichia. coli and diphtheria toxin. We evaluated lasalocid’s capacity to protect cells against other toxins of medical interest comprising toxin B from Clostridium difficile, Shiga-like toxin 1 from enterohemorrhagic E. coli and exotoxin A from Pseudomonas aeruginosa. We further characterized the impact of lasalocid on the endolysosomal and the retrograde pathways and organelle integrity, especially the Golgi apparatus. We found that lasalocid protects cells from all toxins tested and impairs the drop of vesicular pH along the trafficking pathways that are required for toxin sorting and translocation to the cytoplasm. Lasalocid also has an impact on the cellular distribution of GOLPH4 and GOLPH2 Golgi markers. Other intracellular trafficking compartments positive for EEA1 and Rab9A display a modified cellular pattern. In conclusion, lasalocid protects cells from multiple deadly bacterial toxins by corrupting vesicular trafficking and Golgi stack homeostasis.
Nassim Mahtal; Yu Wu; Jean-Christophe Cintrat; Julien Barbier; Emmanuel Lemichez; Daniel Gillet. Revisiting Old Ionophore Lasalocid as a Novel Inhibitor of Multiple Toxins. Toxins 2020, 12, 26 .
AMA StyleNassim Mahtal, Yu Wu, Jean-Christophe Cintrat, Julien Barbier, Emmanuel Lemichez, Daniel Gillet. Revisiting Old Ionophore Lasalocid as a Novel Inhibitor of Multiple Toxins. Toxins. 2020; 12 (1):26.
Chicago/Turabian StyleNassim Mahtal; Yu Wu; Jean-Christophe Cintrat; Julien Barbier; Emmanuel Lemichez; Daniel Gillet. 2020. "Revisiting Old Ionophore Lasalocid as a Novel Inhibitor of Multiple Toxins." Toxins 12, no. 1: 26.
Botulism is a rare but severe neurological disease in man and animals that is caused by botulinum neurotoxins (BoNTs) produced by Clostridium botulinum and atypical strains from other Clostridium and non-Clostridium species. BoNTs are divided into more than seven toxinotypes based on neutralization with specific corresponding antisera, and each toxinotype is subdivided into subtypes according to amino acid sequence variations. Animal species show variable sensitivity to the different BoNT toxinotypes. Thereby, naturally acquired animal botulism is mainly due to BoNT/C, D and the mosaic variants CD and DC, BoNT/CD being more prevalent in birds and BoNT/DC in cattle, whereas human botulism is more frequently in the types A, B and E, and to a lower extent, F. Botulism is not a contagious disease, since there is no direct transmission from diseased animals or man to a healthy subject. Botulism occurs via the environment, notably from food contaminated with C. botulinum spores and preserved in conditions favorable for C. botulinum growth and toxin production. The high prevalence of botulism types C, D and variants DC and CD in farmed and wild birds, and to a lower extent in cattle, raises the risk of transmission to human beings. However, human botulism is much rarer than animal botulism, and botulism types C and D are exceptional in humans. Only 15 cases or suspected cases of botulism type C and one outbreak of botulism type D have been reported in humans to date. In contrast, animal healthy carriers of C. botulinum group II, such as C. botulinum type E in fish of the northern hemisphere, and C. botulinum B4 in pigs, represent a more prevalent risk of botulism transmission to human subjects. Less common botulism types in animals but at risk of transmission to humans, can sporadically be observed, such as botulism type E in farmed chickens in France (1998–2002), botulism type B in cattle in The Netherlands (1977–1979), botulism types A and B in horses, or botulism type A in dairy cows (Egypt, 1976). In most cases, human and animal botulisms have distinct origins, and cross transmissions between animals and human beings are rather rare, accidental events. But, due to the severity of this disease, human and animal botulism requires a careful surveillance.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Public Health Risk Associated with Botulism as Foodborne Zoonoses. Toxins 2019, 12, 17 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Public Health Risk Associated with Botulism as Foodborne Zoonoses. Toxins. 2019; 12 (1):17.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2019. "Public Health Risk Associated with Botulism as Foodborne Zoonoses." Toxins 12, no. 1: 17.
One challenge in cell biology is to decipher the biophysical mechanisms governing protein enrichment on curved membranes and the resulting membrane deformation. The ERM protein ezrin is abundant and associated with cellular membranes that are flat, positively or negatively curved. Using in vitro and cell biology approaches, we assess mechanisms of ezrin’s enrichment on curved membranes. We evidence that wild-type ezrin (ezrinWT) and its phosphomimetic mutant T567D (ezrinTD) do not deform membranes but self-assemble anti-parallelly, zipping adjacent membranes. EzrinTD’s specific conformation reduces intermolecular interactions, allows binding to actin filaments, which reduces membrane tethering, and promotes ezrin binding to positively-curved membranes. While neither ezrinTD nor ezrinWT senses negative curvature alone, we demonstrate that interacting with curvature-sensing I-BAR-domain proteins facilitates ezrin enrichment in negatively-curved membrane protrusions. Overall, our work demonstrates that ezrin can tether membranes, or be targeted to curved membranes, depending on conformations and interactions with actin and curvature-sensing binding partners.
Feng-Ching Tsai; Aurelie Bertin; Hugo Bousquet; John Manzi; Yosuke Senju; Meng-Chen Tsai; Laura Picas; Stephanie Miserey-Lenkei; Pekka Lappalainen; Emmanuel Lemichez; Evelyne Coudrier; Patricia Bassereau. Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner. eLife 2018, 7, 1 .
AMA StyleFeng-Ching Tsai, Aurelie Bertin, Hugo Bousquet, John Manzi, Yosuke Senju, Meng-Chen Tsai, Laura Picas, Stephanie Miserey-Lenkei, Pekka Lappalainen, Emmanuel Lemichez, Evelyne Coudrier, Patricia Bassereau. Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner. eLife. 2018; 7 ():1.
Chicago/Turabian StyleFeng-Ching Tsai; Aurelie Bertin; Hugo Bousquet; John Manzi; Yosuke Senju; Meng-Chen Tsai; Laura Picas; Stephanie Miserey-Lenkei; Pekka Lappalainen; Emmanuel Lemichez; Evelyne Coudrier; Patricia Bassereau. 2018. "Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner." eLife 7, no. : 1.
Botulinum neurotoxins (BoNTs) are the most potent known toxins, and are therefore classified as extremely harmful biological weapons. However, BoNTs are therapeutic drugs that are widely used and have an increasing number of applications. BoNTs show a high diversity and are divided into multiple types and subtypes. Better understanding of the activity at the molecular and clinical levels of the natural BoNT variants as well as the development of BoNT-based chimeric molecules opens the door to novel medical applications such as silencing the sensory neurons at targeted areas and dermal restoration. This short review is focused on BoNTs’ variability and the opportunities or challenges posed for future clinical applications.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Variability of Botulinum Toxins: Challenges and Opportunities for the Future. Toxins 2018, 10, 374 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Variability of Botulinum Toxins: Challenges and Opportunities for the Future. Toxins. 2018; 10 (9):374.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2018. "Variability of Botulinum Toxins: Challenges and Opportunities for the Future." Toxins 10, no. 9: 374.
While genetic evidence points towards an absence of Toll-Like Receptors (TLRs) in Platyhelminthes, the Toll/IL-1 Receptor (TIR)-domains that drive the assembly of signalling complexes downstream TLR are present in these organisms. Here, we undertook the characterisation of the repertoire of TIR-domain containing proteins in Schmidtea mediterranea in order to gain valuable information on TLR evolution in metazoan. We report the presence of twenty proteins containing between one and two TIR domains. In addition, our phylogenetic-based reconstruction approach identified Smed-SARM and Smed-MyD88 as conserved TLR adaptors.
Landry Tsoumtsa; Seynabou Sougoufara; Cédric Torre; Emmanuel Lemichez; Pierre Pontarotti; Eric Ghigo; Seynabou Sougoufoura. In silico analysis of Schmidtea mediterranea TIR domain-containing proteins. Developmental & Comparative Immunology 2018, 86, 214 -218.
AMA StyleLandry Tsoumtsa, Seynabou Sougoufara, Cédric Torre, Emmanuel Lemichez, Pierre Pontarotti, Eric Ghigo, Seynabou Sougoufoura. In silico analysis of Schmidtea mediterranea TIR domain-containing proteins. Developmental & Comparative Immunology. 2018; 86 ():214-218.
Chicago/Turabian StyleLandry Tsoumtsa; Seynabou Sougoufara; Cédric Torre; Emmanuel Lemichez; Pierre Pontarotti; Eric Ghigo; Seynabou Sougoufoura. 2018. "In silico analysis of Schmidtea mediterranea TIR domain-containing proteins." Developmental & Comparative Immunology 86, no. : 214-218.
Nassim Mahtal; Orane Visvikis; Daniel Gillet; Jean-Christophe Cintrat; Emmanuel Lemichez; Julien Barbier. High-Throughput Screening of Rac1 enhancers as stimulators of innate and acquired immunity. Toxicon 2018, 149, 86 -87.
AMA StyleNassim Mahtal, Orane Visvikis, Daniel Gillet, Jean-Christophe Cintrat, Emmanuel Lemichez, Julien Barbier. High-Throughput Screening of Rac1 enhancers as stimulators of innate and acquired immunity. Toxicon. 2018; 149 ():86-87.
Chicago/Turabian StyleNassim Mahtal; Orane Visvikis; Daniel Gillet; Jean-Christophe Cintrat; Emmanuel Lemichez; Julien Barbier. 2018. "High-Throughput Screening of Rac1 enhancers as stimulators of innate and acquired immunity." Toxicon 149, no. : 86-87.
Alterations of the cellular proteome over time due to spontaneous or toxin-mediated enzymatic deamidation of glutamine (Gln) and asparagine (Asn) residues contribute to bacterial infection and might represent a source of aging-related diseases. Here, we put into perspective what is known about the mode of action of the CNF1 toxin from pathogenic Escherichia coli, a paradigm of bacterial deamidases that activate Rho GTPases, to illustrate the importance of determining whether exposure to these factors are risk factors in the etiology age-related diseases, such as cancer. In particular, through in silico analysis of the distribution of the CNF1-like deamidase active site Gly-Cys-(Xaa)n-His sequence motif in bacterial genomes, we unveil the wide distribution of the super-family of CNF-like toxins and CNF-like deamidase domains among members of the Enterobacteriacae and in association with a large variety of toxin delivery systems. We extent our discussion with recent findings concerning cellular systems that control activated Rac1 GTPase stability and provide protection against cancer. These findings point to the urgency for developing holistic approaches toward personalized medicine that include monitoring for asymptomatic carriage of pathogenic toxin-producing bacteria and that ultimately might lead to improved public health and increased lifespans.
Mengfei Ho; Amel Mettouchi; Brenda A Wilson; Emmanuel Lemichez. CNF1-like deamidase domains: common Lego bricks among cancer-promoting immunomodulatory bacterial virulence factors. Pathogens and Disease 2018, 76, 1 .
AMA StyleMengfei Ho, Amel Mettouchi, Brenda A Wilson, Emmanuel Lemichez. CNF1-like deamidase domains: common Lego bricks among cancer-promoting immunomodulatory bacterial virulence factors. Pathogens and Disease. 2018; 76 (5):1.
Chicago/Turabian StyleMengfei Ho; Amel Mettouchi; Brenda A Wilson; Emmanuel Lemichez. 2018. "CNF1-like deamidase domains: common Lego bricks among cancer-promoting immunomodulatory bacterial virulence factors." Pathogens and Disease 76, no. 5: 1.
One challenge in current cell biology is to decipher the biophysical mechanisms governing protein enrichment on curved membranes and the resulting membrane deformation. The ERM protein ezrin is abundant and associated with cellular membranes that are flat or with positive or negative curvatures. Using in vitro and cell biology approaches, we assess mechanisms of ezrin’s enrichment on curved membranes. We evidence that ezrin (ezrinWT) and its phosphomimetic mutant T567D (ezrinTD) do not deform membranes but self-assemble anti-parallelly, zipping adjacent membranes. EzrinTD’s specific conformation reduces intermolecular ezrin interactions, allows binding to actin filaments, and promotes ezrin binding to positively curved membranes. While neither ezrinTD nor ezrinWT senses negative membrane curvature alone, we demonstrate that interacting with curvature sensors I-BAR-domain proteins facilitates ezrin enrichment in negatively curved membrane protrusions. Overall, our work reveals new mechanisms, specific conformation or binding to a curvature sensor partner, for targeting curvature insensitive proteins to curved membranes.
Feng-Ching Tsai; Aurelie Bertin; Hugo Bousquet; John Manzi; Yosuke Senju; Meng-Chen Tsai; Laura Picas; Stéphanie Miserey-Lenkei; Pekka Lappalainen; Emmanuel Lemichez; Evelyne Coudrier; Patricia Bassereau. Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner. 2018, 297895 .
AMA StyleFeng-Ching Tsai, Aurelie Bertin, Hugo Bousquet, John Manzi, Yosuke Senju, Meng-Chen Tsai, Laura Picas, Stéphanie Miserey-Lenkei, Pekka Lappalainen, Emmanuel Lemichez, Evelyne Coudrier, Patricia Bassereau. Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner. . 2018; ():297895.
Chicago/Turabian StyleFeng-Ching Tsai; Aurelie Bertin; Hugo Bousquet; John Manzi; Yosuke Senju; Meng-Chen Tsai; Laura Picas; Stéphanie Miserey-Lenkei; Pekka Lappalainen; Emmanuel Lemichez; Evelyne Coudrier; Patricia Bassereau. 2018. "Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner." , no. : 297895.
The Cytotoxic Necrotizing Factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra-intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation, and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work, we developed a fluorescent, cell-based immunoassay to screen for inhibitors of CNF1-induced Rac1 degradation among 1,120 mostly approved drugs. Eleven compounds prevented CNF1-induced Rac1 degradation and five showed also a protective effect on CNF1-induced multinucleation. At last, lasalocid, monensin, bepridil and amodiaquine protect cells from both diphtheria toxin and CNF1 challenges. These data highlight potential drug repositioning to fight several bacterial toxi-infections and Rac1-based diseases.
Nassim Mahtal; Clémence Brewee; Sylvain Pichard; Orane Visvikis; Jean-Christophe Cintrat; Julien Barbier; Emmanuel Lemichez; Daniel Gillet. Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1. ChemMedChem 2018, 13, 754 -761.
AMA StyleNassim Mahtal, Clémence Brewee, Sylvain Pichard, Orane Visvikis, Jean-Christophe Cintrat, Julien Barbier, Emmanuel Lemichez, Daniel Gillet. Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1. ChemMedChem. 2018; 13 (7):754-761.
Chicago/Turabian StyleNassim Mahtal; Clémence Brewee; Sylvain Pichard; Orane Visvikis; Jean-Christophe Cintrat; Julien Barbier; Emmanuel Lemichez; Daniel Gillet. 2018. "Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1." ChemMedChem 13, no. 7: 754-761.
The regulation of Rac1 by HACE1-mediated ubiquitination and proteasomal degradation is emerging as an essential element in the maintenance of cell homeostasis. However, how the E3 ubiquitin ligase activity of HACE1 is regulated remains undetermined. Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases downstream Rac1 activation by CNF1 toxin from pathogenic E. coli. Moreover, cell treatment with VEGF also promotes Ser-385 phosphorylation of HACE1. We have established in vitro that HACE1 is a direct target of PAK1 kinase activity. Mechanistically, we found that the phospho-mimetic mutant HACE1(S385E), as opposed to HACE1(S385A), displays a lower capacity to ubiquitinate Rac1 in cells. Concomitantly, phosphorylation of Ser-385 plays a pivotal role in controlling the oligomerization state of HACE1. Finally, Ser-385 phosphorylated form of HACE1 localizes in the cytosol away from its target Rac1. Together, our data point to a feedback inhibition of HACE1 ubiquitination activity on Rac1 by group-I PAK kinases.
Maria I. Acosta; Serge Urbach; Anne Doye; Yuen-Wai Ng; Jérôme Boudeau; Amel Mettouchi; Anne Debant; Edward Manser; Orane Visvikis; Emmanuel Lemichez. Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination. Scientific Reports 2018, 8, 1410 .
AMA StyleMaria I. Acosta, Serge Urbach, Anne Doye, Yuen-Wai Ng, Jérôme Boudeau, Amel Mettouchi, Anne Debant, Edward Manser, Orane Visvikis, Emmanuel Lemichez. Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination. Scientific Reports. 2018; 8 (1):1410.
Chicago/Turabian StyleMaria I. Acosta; Serge Urbach; Anne Doye; Yuen-Wai Ng; Jérôme Boudeau; Amel Mettouchi; Anne Debant; Edward Manser; Orane Visvikis; Emmanuel Lemichez. 2018. "Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination." Scientific Reports 8, no. 1: 1410.
Sandrine Bourdoulous; Emmanuel Lemichez. Decoding glycan recognition by bacterial toxins. Nature Microbiology 2018, 3, 124 -126.
AMA StyleSandrine Bourdoulous, Emmanuel Lemichez. Decoding glycan recognition by bacterial toxins. Nature Microbiology. 2018; 3 (2):124-126.
Chicago/Turabian StyleSandrine Bourdoulous; Emmanuel Lemichez. 2018. "Decoding glycan recognition by bacterial toxins." Nature Microbiology 3, no. 2: 124-126.
The following sections are included:
Emmanuel Lemichez; Amel Mettouchi; Michel Robert Popoff. Posttranslational modifications of Rho GTPases mediated by bacterial toxins and cellular systems. Rho GTPases 2017, 97 -118.
AMA StyleEmmanuel Lemichez, Amel Mettouchi, Michel Robert Popoff. Posttranslational modifications of Rho GTPases mediated by bacterial toxins and cellular systems. Rho GTPases. 2017; ():97-118.
Chicago/Turabian StyleEmmanuel Lemichez; Amel Mettouchi; Michel Robert Popoff. 2017. "Posttranslational modifications of Rho GTPases mediated by bacterial toxins and cellular systems." Rho GTPases , no. : 97-118.