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Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.
Imbalances in secretory proteostasis induced by genetic, environmental, or aging-related insults are pathologically associated with etiologically diverse protein misfolding diseases. To protect the secretory proteome from these insults, organisms evolved stress-responsive signaling pathways that regulate the composition and activity of biologic pathways involved in secretory proteostasis maintenance. The most prominent of these is the endoplasmic reticulum (ER) unfolded protein response (UPR), which functions to regulate ER proteostasis in response to ER stress. While the signaling mechanisms involved in UPR activation are well defined, the impact of UPR activation on secretory proteostasis is only now becoming clear. Here, we highlight recent reports defining how activation of select UPR signaling pathways influences proteostasis within the ER and downstream secretory environments. Furthermore, we describe recent evidence that highlights the therapeutic potential for targeting UPR signaling pathways to correct pathologic disruption in secretory proteostasis associated with diverse types of protein misfolding diseases.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Unconventional secretion of exosome vesicles from multivesicular endosomes (MVEs) occurs across a broad set of systems and is reported to be upregulated in cancer, where it promotes aggressive behavior. However, regulatory control of exosome secretion is poorly understood. Using cancer cells, we identified specialized invasive actin structures called invadopodia as specific and critical docking and secretion sites for CD63- and Rab27a-positive MVEs. Thus, inhibition of invadopodia formation greatly reduced exosome secretion into conditioned media. Functionally, addition of purified exosomes or inhibition of exosome biogenesis or secretion greatly affected multiple invadopodia life cycle steps, including invadopodia formation, stabilization, and exocytosis of proteinases, indicating a key role for exosome cargoes in promoting invasive activity and providing in situ signaling feedback. Exosome secretion also controlled cellular invasion through three-dimensional matrix. These data identify a synergistic interaction between invadopodia biogenesis and exosome secretion and reveal a fundamental role for exosomes in promoting cancer cell invasiveness.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
In mammals an increase in glucose leads to block of ATP dependent potassium channels in pancreatic β cells leading to membrane depolarization. This leads to the repetitive firing of action potentials that increases calcium influx and triggers insulin granule exocytosis. Several important differences between species in this process suggest that a dedicated human-oriented approach is advantageous as extrapolating from rodent data may be misleading in several respects. We examined depolarization-induced spike activity in pancreatic human islet-attached β-cells employing whole-cell patch-clamp methods. We also reviewed the literature concerning regulation of insulin secretion by channel activity and constructed a data-based computer model of human β cell function. The model couples the Hodgkin-Huxley-type ionic equations to the equations describing intracellular Ca²⁺ homeostasis and insulin release. On the basis of this model we employed computational simulations to better understand the behavior of action potentials, calcium handling and insulin secretion in human β cells under a wide range of experimental conditions. This computational system approach provides a framework to analyze the mechanisms of human β cell insulin secretion.
The genus Acinetobacter is comprised of a diverse group of species, several of which have raised interest due to potential applications in bioremediation and agricultural purposes. In this work, we show that many species within the genus Acinetobacter possess the genetic requirements to assemble a functional type VI secretion system (T6SS). This secretion system is widespread among Gram negative bacteria, and can be used for toxicity against other bacteria and eukaryotic cells. The most studied species within this genus is A. baumannii, an emerging nosocomial pathogen that has become a significant threat to healthcare systems worldwide. The ability of A. baumannii to develop multidrug resistance has severely reduced treatment options, and strains resistant to most clinically useful antibiotics are frequently being isolated. Despite the widespread dissemination of A. baumannii, little is known about the virulence factors this bacterium utilizes to cause infection. We determined that the T6SS is conserved and syntenic among A. baumannii strains, although expression and secretion of the hallmark protein Hcp varies between strains, and is dependent on TssM, a known structural protein required for T6SS function. Unlike other bacteria, A. baumannii ATCC 17978 does not appear to use its T6SS to kill Escherichia coli or other Acinetobacter species. Deletion of tssM does not affect virulence in several infection models, including mice, and did not alter biofilm formation. These results suggest that the T6SS fulfils an important but as-yet-unidentified role in the various lifestyles of the Acinetobacter spp.
Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through G(i) activation of Y(1) and SSTR(1&5) receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca(2+)](i)) activity upon glucose stimulation, whereas SST alters this response. G(βγ)-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca(2+)](i). mSIRK-induced G(βγ) activation does not modulate glucose metabolism but increases [Ca(2+)](i) activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through G(βγ) inhibition of Ca(2+) activity, while NPY activates a Ca(2+)-independent pathway mediated by G(α). GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies.
AIMS/HYPOTHESIS - Our understanding of the transcription factors that control the development and function of rodent islet beta cells is advancing rapidly, yet less is known of the role they play in similar processes in human islets.
METHODS - To characterise the abundance and regulation of key proteins involved in glucose-regulated insulin secretion in human islets, we examined the expression of MAFA, MAFB, GLUT2 (also known as SLC2A2), βGK (also known as GCK) and PDX1 in isolated, highly purified human islets with an intact insulin secretory pattern. We also assessed these features in islets from two different mouse strains (C57BL/6J and FVB).
RESULTS - Compared with mouse islets, human islets secreted more insulin at baseline glucose (5.6 mmol/l), but less upon stimulation with high glucose (16.7 mmol/l) or high glucose plus 3-isobutyl-1-methyl-xanthine. Human islets had relatively more MAFB than PDX1 mRNA, while mouse islets had relatively more Pdx1 than Mafb mRNA. However, v-maf musculoaponeurotic fibrosarcoma oncogene homologue (MAF) B protein was found in human islet alpha and beta cells. This is unusual as this regulator is only produced in islet alpha cells in adult mice. The expression of insulin, MAFA, βGK and PDX1 was not glucose-regulated in human islets with an intact insulin secretory pattern.
CONCLUSIONS/INTERPRETATION - Our results suggest that human islets have a distinctive distribution and function of key regulators of the glucose-stimulated insulin secretion pathway, emphasising the urgent need to understand the processes that regulate human islet beta cell function.
BACKGROUND - Diseases caused by gammaherpesviruses continue to be a challenge for human health and antiviral treatment. Most of the commonly used antiviral drugs are directed against viral gene products. However, the emergence of drug-resistant mutations ma limit the effectiveness of these drugs. Since viruses require a host cell to propagate, the search for host cell targets is an interesting alternative.
METHODS - In this study, we infected three different cell types (fibroblasts, endothelial precursor cells and macrophages with a murine gammaherpesvirus and analysed the host cell response for changes either common to all or unique to a particular cell type using oligonucleotide microarrays.
RESULTS - The analysis revealed a number of genes whose transcription was significantly up- or down-regulated in either one or two of the cell types tested. After infection, only two genes, Lman1 (also known as ERGIC53) an synaptobrevin-like 1 (sybl1) were significantly up-regulated in all three cell types, suggestive for a general role for the virus life cycl independent of the cell type. Both proteins have been implicated in cellular exocytosis and transport of glycoproteins through the secretory pathway. To test the significance of the observed up-regulation, the functionality of these proteins was modulated, and the effect on virus replication was monitored. Inhibition of either Lman1 or sybl1 resulted in a significant reduction in virus production.
CONCLUSIONS - This suggests that proteins of the secretory pathway which appear to be rate limiting for virus production may represent new targets for intervention.