Pleistocene Tectono-magmato-volcanic events recorded east of Mayotte - insights for the ongoing seismo-volcanic crisis

The offshore eastern Mayotte area has been extensively studied since the outbreak of the seismo-volcanic crisis in May 2018. Several oceanographic surveys have been carried out by REVOSIMA – https://doi.org/10.18715/MAYOTTE.REVOSIMA (MAYOBS cruises -https://doi.org/10.18142/291) for monitoring purpose, or for academic research (SISMAORE - https://doi.org/10.17600/18001331 and SCRATCH cruises - https://doi.org/10.17600/18002274). They offer a complete coverage of the eastern slope and abyssal plain with multibeam bathymetry and backscatter imagery, sub-bottom profiler (SBP), and several sediment cores. This set of data offers the opportunity to describe the morphology of the area and details the first tens of meters of the sedimentary succession on the abyssal plain.We discover several features including faults, domes and massive chaotic deposits that developed or occurred during Quaternary in the vicinity of the new Fani Maore Volcano. Domes are interpreted as forced folds related to the intrusion of a large sill at depth. The main fault crossing the largest forced fold is a succession of en-echelon segments with vertical throws of up to 8 meters and a preferential N130° strike compatible with the present day regional dextral context. Analysis of the SBP profiles reveals that faulting and doming associated to sill intrusion occurred simultaneously, and together with the deposition of two massive (several km3) and chaotic lobes at the foot of the Mayotte slope. Sediment cores collected over or close to the massive deposits indicate a mixed bioclastic-volcanoclastic content with a large amount of pumices, whose aspect and chemical composition are identical to volcanic edifices located on the upper slope (Horseshoe Volcano) or onshore (Petite-Terre). Backscatter imagery also reveals streaks that cover the lobes and trace back to the same upper slope area. Analysis of bioclasts from a core catcher stopped in the upper part of the deposit shows a large variety of foraminifers, shells fragments, with a little proportion originating from the upper-slope and shelf. We propose that these massive lobe deposits might have occurred as the pumice-dominated material ejected at HV or PT flows downslope, thus reworking and incorporating a substantial amount of hemipelagic deposits along the slope and over the abyssal plain. These observations suggests that a tectono-magmato-volcanic event occurred during recent geological time (Late Pleistocene according to early estimations). At least one comparable set of similar and synchronous features appears on our dataset thus implying the occurrence of a similar event, earlier in the Pleistocene. The correlations between these events and the activity at HV and PT volcanic centers are critical, as it would provide a recurring scenario to compare with present day seismo-volcanic crisis at Mayotte.This work is funded by REVOSIMA, ANR funded COYOTES project, and internal BRGM Project PDEV MAYOTTE.COmores & maYotte : vOlcanisme, TEctonique et Sismicit

The <i>N</i>-myristoylome of <i>Trypanosoma cruzi</i>

Protein N-myristoylation is catalysed by N-myristoyltransferase (NMT), an essential and druggable target in Trypanosoma cruzi, the causative agent of Chagas’ disease. Here we have employed whole cell labelling with azidomyristic acid and click chemistry to identify N-myristoylated proteins in different life cycle stages of the parasite. Only minor differences in fluorescent-labelling were observed between the dividing forms (the insect epimastigote and mammalian amastigote stages) and the non-dividing trypomastigote stage. Using a combination of label-free and stable isotope labelling of cells in culture (SILAC) based proteomic strategies in the presence and absence of the NMT inhibitor DDD85646, we identified 56 proteins enriched in at least two out of the three experimental approaches. Of these, 6 were likely to be false positives, with the remaining 50 commencing with amino acids MG at the N-terminus in one or more of the T. cruzi genomes. Most of these are proteins of unknown function (32), with the remainder (18) implicated in a diverse range of critical cellular and metabolic functions such as intracellular transport, cell signalling and protein turnover. In summary, we have established that 0.43–0.46% of the proteome is N-myristoylated in T. cruzi approaching that of other eukaryotic organisms (0.5–1.7%)

Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus

Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections

Targeting N-myristoylation for therapy of B-cell lymphomas

N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients

Formation and deformation of hyperextended rift systems: Insights from rift domain mapping in the Bay of Biscay-Pyrenees

International audienceThe Bay of Biscay and the Pyrenees correspond to a Lower Cretaceous rift system including both oceanic and hyperextended rift domains. The transition from preserved oceanic and rift domains in the West to their complete inversion in the East enables us to study the progressive reactivation of a hyperextended rift system. We use seismic interpretation, gravity inversion, and field mapping to identify and map former rift domains and their subsequent reactivation. We propose a new map and sections across the system illustrating the progressive integration of the rift domains into the orogen. This study aims to provide insights on the formation of hyperextended rift systems and discuss their role during reactivation. Two spatially and temporally distinct rift systems can be distinguished: the Bay of Biscay-Parentis and the Pyrenean-Basque-Cantabrian rifts. While the offshore Bay of Biscay represent a former mature oceanic domain, the fossil remnants of hyperextended domains preserved onshore in the Pyrenean-Cantabrian orogen record distributed extensional deformation partitioned between strongly segmented rift basins. Reactivation initiated in the exhumed mantle domain before it affected the hyperthinned domain. Both domains accommodated most of the shortening. The final architecture of the orogen is acquired once the conjugate necking domains became involved in collisional processes. The complex 3-D architecture of the initial rift system may partly explain the heterogeneous reactivation of the overall system. These results have important implications for the formation and reactivation of hyperextended rift systems and for the restoration of the Bay of Biscay and Pyrenean domain

Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation

A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules

N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells

N-Myristoyltransferase (NMT) covalently attaches a C14-fatty acid to the N-terminal glycine of proteins and has been proposed as a therapeutic target in cancer. We have recently shown that selective NMT inhibition leads to dose-responsive loss of N-myristoylation on more than 100 protein targets in cells, and cytotoxicity in cancer cells. N-myristoylation lies upstream of multiple pro-proliferative and oncogenic pathways, but to date the complex substrate specificity of NMT has limited determination of which diseases are most likely to respond to a selective NMT inhibitor. We describe here the phenotype of NMT inhibition in HeLa cells, and show that cells die through apoptosis following or concurrent with accumulation in G1 phase. We used quantitative proteomics to map protein expression changes for more than 2700 proteins in response to treatment with an NMT inhibitor in HeLa cells, and observed down-regulation of proteins involved in cell cycle regulation, and up-regulation of proteins involved in the endoplasmic reticulum stress and unfolded protein response, with similar results in breast (MCF-7, MDA-MB-231) and colon (HCT116) cancer cell lines. This study describes the cellular response to NMT inhibition at the proteome level, and provides a starting point for selective targeting of specific diseases with NMT inhibitors, potentially in combination with other targeted agents

Click chemistry armed enzyme-linked immunosorbent assay to measure palmitoylation by hedgehog acyltransferase

AbstractHedgehog signaling is critical for correct embryogenesis and tissue development. However, on maturation, signaling is also found to be aberrantly activated in many cancers. Palmitoylation of the secreted signaling protein sonic hedgehog (Shh) by the enzyme hedgehog acyltransferase (Hhat) is required for functional signaling. To quantify this important posttranslational modification, many in vitro Shh palmitoylation assays employ radiolabeled fatty acids, which have limitations in terms of cost and safety. Here we present a click chemistry armed enzyme-linked immunosorbent assay (click–ELISA) for assessment of Hhat activity through acylation of biotinylated Shh peptide with an alkyne-tagged palmitoyl-CoA (coenzyme A) analogue. Click chemistry functionalization of the alkyne tag with azido-FLAG peptide allows analysis through an ELISA protocol and colorimetric readout. This assay format identified the detergent n-dodecyl β-d-maltopyranoside as an improved solubilizing agent for Hhat activity. Quantification of the potency of RU-SKI small molecule Hhat inhibitors by click–ELISA indicated IC50 values in the low- or sub-micromolar range. A stopped assay format was also employed that allows measurement of Hhat kinetic parameters where saturating substrate concentrations exceed the binding capacity of the streptavidin-coated plate. Therefore, click–ELISA represents a nonradioactive method for assessing protein palmitoylation in vitro that is readily expandable to other classes of protein lipidation