Identification of Restricted Subsets of Mature microRNA Abnormally Expressed in Inactive Colonic Mucosa of Patients with Inflammatory Bowel Disease

International audienceBACKGROUND: Ulcerative Colitis (UC) and Crohn's Disease (CD) are two chronic Inflammatory Bowel Diseases (IBD) affecting the intestinal mucosa. Current understanding of IBD pathogenesis points out the interplay of genetic events and environmental cues in the dysregulated immune response. We hypothesized that dysregulated microRNA (miRNA) expression may contribute to IBD pathogenesis. miRNAs are small, non-coding RNAs which prevent protein synthesis through translational suppression or mRNAs degradation, and regulate several physiological processes. METHODOLOGY/FINDINGS: Expression of mature miRNAs was studied by Q-PCR in inactive colonic mucosa of patients with UC (8), CD (8) and expressed relative to that observed in healthy controls (10). Only miRNAs with highly altered expression (>5 or 100 -fold and 0.05-0.19 -fold for over- and under- expression, respectively; 0.00

Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation

International audienceAnterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses

La N-glycosylation: marqueur precoce de la differenciation enterocytaire des cellules HT-29

SIGLEINIST T 74159 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

MicroARN et physiopathologie intestinale

Les microARN (miARN) constituent une classe de petits ARN non codants d’environ 20 nucléotides qui contrôlent négativement l’expression d’ARN messagers cibles. Les eucaryotes multicellulaires utilisent les miARN pour contrôler leurs fonctions vitales, différenciation, prolifération ou apoptose. La diversité des miARN et le nombre considérable de leurs ARN messagers cibles en font des acteurs importants de la régulation de l’expression génique. Des études récentes ont révélé que l’expression anormale des miARN représente une caractéristique commune des cellules cancéreuses et que ces miARN peuvent fonctionner comme des gènes suppresseurs de tumeur ou des oncogènes. Cette revue fait le point des travaux portant sur l’implication des miARN dans la pathogénie des cancers colorectaux. Le rôle des miARN dans le contrôle de l’inflammation et leur implication potentielle dans les pathologies inflammatoires intestinales sont aussi discutés

A Turing mechanism in order to explain the patchy nature of Crohn’s disease

International audienc

The cecal appendix is correlated with greater maximal longevity in mammals

International audienceThe cecal appendix had been considered as a useless vestige since Darwin's work, but recent research questioned this idea demonstrating that the cecal appendix appeared among the mammals at least 80 million years ago and has made multiple and independent appearances without any obvious correlation with diet, social life, ecology, or size of the cecum. However, functions and probable selective advantage conferred by this anatomical structure still remain enigmatic. We found, through analyses of data on 258 mammalian species, that cecal appendix presence is correlated with increased maximal observed longevity. This is the first demonstration of a correlation between cecal appendix presence and life history. Interestingly, the classical evolutionary theory of aging that predicts an increased longevity when the extrinsic mortality is reduced has been questioned several times, but recent comparative studies asserted its validity in the taxa, which experience age-dependent and density-dependent mortality, as in mammals. Thus, the cecal appendix may contribute to the increase in longevity through a reduction of extrinsic mortality. A lower risk of fatal infectious diarrhea is one of the most plausible hypotheses that could explain it. However, several hypotheses coexist about the possible functions of the cecal appendix, and our results provide new insights about this much-disputed question. In addition, we show that the cecal appendix arose at least 16 times and was lost only once during the evolutionary history of the considered mammals, an asymmetry that supports the existence of a positive selective of this structure

MicroRNAs and intestinal pathophysiology

MicroRNAs (miRNAs) represent an abundant class of endogenously expressed small RNAs, which is believed to control the expression of proteins through specific interaction with their mRNAs. MiRNAs are non-coding RNAs of 18 to 24 nucleotides that negatively regulate target mRNAs by binding to their 3'-untranslated regions (UTR). Most eukaryotic cells utilize miRNA to regulate vital functions such as cell differentiation, proliferation or apopotosis. The diversity of miRNAs and of their mRNA targets strongly indicate that they play a key role in the regulation of protein expression. To date, more than 500 different miRNAs have been identified in animals and plants. There are at least 326 miRNAs in the human genome, comprising 1-4% of all expressed human genes, which makes miRNAs one of the largest classes of gene regulators. A single miRNA can bind to and regulate many different mRNA targets and, conversely, several different miRNAs can bind to and cooperatively control a single mRNA target. The correlation between the expression of miRNAs and their effects on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidences. Recent studies showed that abnormal expression of miRNAs represents a common feature of cancer cells and that they can function as tumor suppressor genes or as oncogenes. Therefore, this diversity of action for miRNAs on several target genes could be one of the common mechanisms involved in the deregulation of protein expression observed during intestinal disorders. In this review, the emergent functions of miRNAs in colorectal cancer and their potential role in the intestinal inflammatory process are discussed

Modulation of PDI Functions by Localization: The Example of the Anterior Gradient Family

International audienceSignificance: Oxidative folding within the endoplasmic reticulum (ER) introduces disulfide bonds into nascent polypeptides, ensuring proteins' stability and proper functioning. Consequently, this process is critical for maintaining proteome integrity and overall health. The productive folding of thousands of secretory proteins requires stringent quality control measures, such as the Unfolded Protein Response (UPR) and ER-Associated Degradation (ERAD), which contribute significantly to maintaining ER homeostasis. ER-localised protein disulfide isomerases (PDI) play an essential role in each of these processes, thereby contributing to various aspects of ER homeostasis, including maintaining redox balance, proper protein folding, and signaling from the ER to the nucleus.Recent advances: Over the years, there have been increasing reports of the (re)localization of PDI family members and other ER-localized proteins to various compartments. A prime example is the Anterior gradient (AGR) family of PDI proteins, which have been reported to relocate to the cytosol or the extracellular environment, acquiring gain of functions that intersect with various cellular signaling pathways.Critical issues: Here, we summarize the functions of PDIs and their gain or loss of functions in non-ER locations. We will focus on the activity, localization, and function of the AGR proteins: AGR1, AGR2, and AGR3.Future direction: Targeting PDIs in general and AGRs in particular is a promising strategy in different human diseases. Thus, there is a need for innovative strategies and tools aimed at targeting PDIs; those strategies should integrate the specific localization and newly acquired functions of these PDIs rather than solely focusing on their canonical roles

Les Nox/Duox : une nouvelle famille de NADPH oxydases

La production des formes réactives de l’oxygène par la NADPH oxydase phagocytaire a été longtemps considérée comme restreinte aux phagocytes professionnels. Récemment, six homologues de la sous-unité catalytique de la NADPH oxydase phagocytaire (gp91phox ou Nox-2) ont été identifiés et appartiennent à la famille des Nox : Nox-1, Nox-3, Nox-4, Nox-5, Duox-1 et Duox-2. Ces enzymes ont la capacité de transporter des électrons à travers la membrane plasmique et produisent de l’anion superoxyde, luimême précurseur des autres formes réactives de l’oxygène. Cependant, la distribution tissulaire et les mécanismes d’activation des membres de la famille Nox sont très différents, suggérant qu’ils exercent des fonctions physiologiques distinctes dans des mécanismes aussi variés que la défense de l’hôte, la croissance, la différenciation et l’apoptose. La modulation de la fonction des différentes Nox peut être à l’origine d’une grande variété d’événements physiopathologiques