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Kirsty M Hooper, Victor Casanova, Sadie Kemp, Katherine A Staines, Jack Satsangi, Peter G Barlow, Paul Henderson, Craig Stevens
BACKGROUND: Genetic studies have strongly linked autophagy to Crohn's disease (CD), and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process. METHODS: Autophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry...
March 19, 2019: Inflammatory Bowel Diseases
Ellen Li, Yuanhao Zhang, Xinyu Tian, Xuefeng Wang, Grace Gathungu, Ashley Wolber, Shehzad S Shiekh, R Balfour Sartor, Nicholas O Davidson, Matthew A Ciorba, Wei Zhu, Leah M Nelson, Charles E Robertson, Daniel N Frank
We have previously identified NOD2 genotype and inflammatory bowel diseases (IBD) phenotype, as associated with shifts in the ileal microbiome ("dysbiosis") in a patient cohort. Here we report an integrative analysis of an expanded number of Crohn's disease (CD) related genetic defects in innate immune function (NOD2, ATG16L1, IRGM, CARD9, XBP1, ORMDL3) and composition of the ileal microbiome by combining the initial patient cohort (Batch 1, 2005-2010, n = 165) with a second consecutive patient cohort (Batch 2, 2010-2012, n = 118)...
2019: PloS One
Emily J Jones, Zoe J Matthews, Lejla Gul, Padhmanand Sudhakar, Agatha Treveil, Devina Divekar, Jasmine Buck, Tomasz Wrzesinski, Matthew Jefferson, Stuart D Armstrong, Lindsay J Hall, Alastair J M Watson, Simon R Carding, Wilfried Haerty, Federica Di Palma, Ulrike Mayer, Penny P Powell, Isabelle Hautefort, Tom Wileman, Tamas Korcsmaros
Paneth cells are key epithelial cells providing an antimicrobial barrier and maintaining integrity of the small intestinal stem cell niche. Paneth cell abnormalities are unfortunately detrimental to gut health and often associated with digestive pathologies such as Crohn's disease or infections. Similar alterations are observed in individuals with impaired autophagy, a process which recycles cellular components. The direct effect of autophagy-impairment on Paneth cells has not been analysed. To investigate this, we generated a mouse model lacking Atg16l1 specifically in intestinal epithelial cells making these cells impaired in autophagy...
February 27, 2019: Disease Models & Mechanisms
Livia W Brier, Liang Ge, Goran Stjepanovic, Ashley M Thelen, James Hurley, Randy Schekman
Autophagy is a conserved eukaryotic pathway critical for cellular adaptation to changes in nutrition levels and stress. The class III phosphatidylinositol 3-kinase complexes I and II (PI3KC3-C1 and C2) are essential for autophagosome initiation and maturation, respectively, from highly curved vesicles. We used a cell-free reaction that reproduces a key autophagy initiation step, LC3 lipidation, as a biochemical readout to probe the role of ATG14, a PI3KC3-C1-specific subunit implicated in targeting the complex to autophagy initiation sites...
February 27, 2019: Molecular Biology of the Cell
Joel M J Tan, Nora Mellouk, John H Brumell
There is growing evidence in the literature for unconventional roles of autophagy-related (ATG) proteins, outside of their function in canonical autophagy. Here we discuss our recent study that revealed a novel ATG16L1-dependent pathway that promotes plasma membrane repair upon bacterial pore-forming toxin damage. Disruption of the ATG16L1-dependent pathway leads to an accumulation of cholesterol in lysosomes, which affects lysosomal exocytosis required for efficient membrane repair. Our study provides insights into the role of ATG16L1 in cholesterol homeostasis and plasma membrane integrity...
February 26, 2019: Autophagy
Alf Håkon Lystad, Sven R Carlsson, Laura R de la Ballina, Karlina J Kauffman, Shanta Nag, Tamotsu Yoshimori, Thomas J Melia, Anne Simonsen
Covalent modification of LC3 and GABARAP proteins to phosphatidylethanolamine in the double-membrane phagophore is a key event in the early phase of macroautophagy, but can also occur on single-membrane structures. In both cases this involves transfer of LC3/GABARAP from ATG3 to phosphatidylethanolamine at the target membrane. Here we have purified the full-length human ATG12-5-ATG16L1 complex and show its essential role in LC3B/GABARAP lipidation in vitro. We have identified two functionally distinct membrane-binding regions in ATG16L1...
February 18, 2019: Nature Cell Biology
Aurora Scrivo, Patrice Codogno, Pascale Bomont
Autophagy is an essential self-digestion machinery for cell survival and homoeostasis. Membrane elongation is fundamental, as it drives the formation of the double-membrane vesicles that engulf cytosolic material. LC3-lipidation, the signature of autophagosome formation, results from a complex ubiquitin-conjugating cascade orchestrated by the ATG16L1 protein, whose regulation is unknown. Here, we identify the Gigaxonin-E3 ligase as the first regulator of ATG16L1 turn-over and autophagosome production. Gigaxonin interacts with the WD40 domain of ATG16L1 to drive its ubiquitination and subsequent degradation...
February 15, 2019: Nature Communications
Ben C King, Erik Renström, Anna M Blom
Complement component C3 is central to the complement system, a humoral effector mechanism of innate immune defense. When activated, C3 covalently binds to target particles, marking them for uptake and clearance by phagocytosis. We now show that C3 also exists within the cytosol where it interacts with ATG16L1, and is therefore involved in the intracellular clearance and recycling of material by macroautophagy/autophagy in pancreatic beta cells. C3 is highly expressed in isolated human islets, and its expression is upregulated in islets isolated from diabetic patients and rodents, and correlates with patient HBA1c and body mass index (BMI)...
February 11, 2019: Autophagy
Shengnan Xu, Kathryn E Ware, Yuantong Ding, So Young Kim, Maya U Sheth, Sneha Rao, Wesley Chan, Andrew J Armstrong, William C Eward, Mohit Kumar Jolly, Jason A Somarelli
The evolution of therapeutic resistance is a major cause of death for cancer patients. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure of the host immune system. These selective forces often lead to evolutionary convergence on pathways or hallmarks that drive progression. Thus, a deeper understanding of the evolutionary convergences that occur could reveal vulnerabilities to treat therapy-resistant cancer. To this end, we combined phylogenetic clustering, systems biology analyses, and molecular experimentation to identify convergences in gene expression data onto common signaling pathways...
February 7, 2019: Journal of Clinical Medicine
Nora J Foegeding, Krishnan Raghunathan, Anne M Campbell, Sun Wook Kim, Ken S Lau, Anne K Kenworthy, Timothy L Cover, Melanie D Ohi
Helicobacter pylori VacA is a secreted pore-forming toxin that induces cell vacuolation in vitro and contributes to the pathogenesis of gastric cancer and peptic ulcer disease. We observed that purified VacA has relatively little effect on the viability of AGS gastric epithelial cells, but the presence of exogenous weak bases such as ammonium chloride (NH4 Cl) enhances the susceptibility of these cells to VacA-induced vacuolation and cell death. Therefore, we tested the hypothesis that NH4 Cl augments VacA toxicity by altering the intracellular trafficking of VacA or inhibiting intracellular VacA degradation...
January 28, 2019: Infection and Immunity
Sup Kim, Hyuk Soo Eun, Eun-Kyeong Jo
Autophagy is an intracellular catabolic process that is essential for a variety of cellular responses. Due to its role in the maintenance of biological homeostasis in conditions of stress, dysregulation or disruption of autophagy may be linked to human diseases such as inflammatory bowel disease (IBD). IBD is a complicated inflammatory colitis disorder; Crohn's disease and ulcerative colitis are the principal types. Genetic studies have shown the clinical relevance of several autophagy-related genes (ATGs) in the pathogenesis of IBD...
January 21, 2019: Cells
Sydney Lavoie, Kara L Conway, Kara G Lassen, Humberto B Jijon, Hui Pan, Eunyoung Chun, Monia Michaud, Jessica K Lang, Carey Ann Gallini Comeau, Jonathan M Dreyfuss, Jonathan N Glickman, Hera Vlamakis, Ashwin Ananthakrishnan, Aleksander Kostic, Wendy S Garrett, Ramnik J Xavier
Inflammatory bowel disease (IBD) is driven by dysfunction between host genetics, the microbiota, and immune system. Knowledge gaps remain regarding how IBD genetic risk loci drive gut microbiota changes. The Crohn's disease risk allele ATG16L1 T300A results in abnormal Paneth cells due to decreased selective autophagy, increased cytokine release, and decreased intracellular bacterial clearance. To unravel the effects of ATG16L1 T300A on the microbiota and immune system, we employed a gnotobiotic model using human fecal transfers into ATG16L1 T300A knock-in mice...
January 22, 2019: ELife
Wei Wan, Wei Liu
WIPI2 contributes to autophagy by recruiting the ATG12-ATG5-ATG16L1 complex to PtdIns3P-rich membranes, which enables the growth and elongation of phagophores. So far, PtdIns3P and ATG16L1 are the best known WIPI2 interaction partners. In the screening of novel binding proteins for WIPI2, we recently identified interactions between WIPI2 and MTORC1 and the E3 ubiquitin ligase HUWE1. With this clue, we uncovered that WIPI2 is a phosphorylation substrate of MTORC1 and a ubiquitination target of HUWE1. Further, by determining the phosphorylation site on WIPI2 targeted by MTORC1, we show that MTORC1-dependent phosphorylation directs WIPI2 to interact with HUWE1, leading to WIPI2 ubiquitination and subsequent degradation by proteasomes...
January 15, 2019: Autophagy
Jiaranai Peantum, Areerat Kunanopparat, Nattiya Hirankarn, Pisit Tangkijvanich, Ingorn Kimkong
Background: Hepatocellular carcinoma (HCC) as primary malignancy of the liver has become the most common type of cancer worldwide. HCC development is mainly caused by viruses, especially the hepatitis B virus (HBV). Autophagy is an important defense mechanism against virus infection; however, HBV promotes autophagy mediated by the HBx protein which stimulates its replication. The autophagy-related protein 16-1 (ATG16L1) binds to the ATG12-ATG5 conjugate and forms a large protein autophagosome complex...
December 2018: Gastroenterology Research
Miriam Toledo, Rajat Singh
Autophagy prevents pancreatic β cell death during obesity, although the mechanism of autophagy activation in the β cell has remained elusive. In this issue of Cell Metabolism, King et al. (2018) show that intracellular complement component C3 interacts with autophagy protein ATG16L1 and protects against β cell death by stimulating autophagy.
January 8, 2019: Cell Metabolism
Tomoya Iida, Yoshihiro Yokoyama, Kohei Wagatsuma, Daisuke Hirayama, Hiroshi Nakase
Autophagy, an intracellular degradation mechanism, has many immunological functions and is a constitutive process necessary for maintaining cellular homeostasis and organ structure. One of the functions of autophagy is to control the innate immune response. Many studies conducted in recent years have revealed the contribution of autophagy to the innate immune response, and relationships between this process and various diseases have been reported. Inflammatory bowel disease is an intractable disorder with unknown etiology; however, immunological abnormalities in the intestines are known to be involved in the pathology of inflammatory bowel disease, as is dysfunction of autophagy...
December 22, 2018: Cells
Joel M J Tan, Nora Mellouk, Suzanne E Osborne, Dustin A Ammendolia, Diana N Dyer, Ren Li, Diede Brunen, Jorik M van Rijn, Ju Huang, Mark A Czuczman, Marija A Cemma, Amy M Won, Christopher M Yip, Ramnik J Xavier, Donna A MacDuff, Fulvio Reggiori, Jayanta Debnath, Tamotsu Yoshimori, Peter K Kim, Gregory D Fairn, Etienne Coyaud, Brian Raught, Aleixo M Muise, Darren E Higgins, John H Brumell
Plasma membrane integrity is essential for the viability of eukaryotic cells. In response to bacterial pore-forming toxins, disrupted regions of the membrane are rapidly repaired. However, the pathways that mediate plasma membrane repair are unclear. Here we show that autophagy-related (ATG) protein ATG16L1 and its binding partners ATG5 and ATG12 are required for plasma membrane repair through a pathway independent of macroautophagy. ATG16L1 is required for lysosome fusion with the plasma membrane and blebbing responses that promote membrane repair...
December 2018: Nature Microbiology
Ferenc Sipos, Anna L Kiss, Miklós Constantinovits, Zsolt Tulassay, Györgyi Műzes
In relation of immunobiology, the consequence of the crosstalk between TLR9-signaling and autophagy is poorly documented in HT29 cancer cells. To assess the TLR9-mediated biologic effects of modified self-DNA sequences on cell kinetics and autophagy response HT29 cells were incubated separately with intact genomic (g), hypermethylated (m), fragmented (f), and hypermethylated/fragmented (m/f) self-DNAs. Cell viability, apoptosis, cell proliferation, colonosphere-formation were determined. Moreover, the relation of TLR9-signaling to autophagy response was assayed by real-time RT-PCR, immunocytochemistry and transmission electron microscopy (TEM)...
November 21, 2018: Pathology Oncology Research: POR
Martha Zakrzewski, Lisa A Simms, Allison Brown, Mark Appleyard, James Irwin, Nicola Waddell, Graham L Radford-Smith
Background and aims: This study aimed to characterise the mucosa-associated microbiota in ileal Crohn's disease (CD) patients and in healthy controls in terms of host genotype and inflammation status. Methods: The mucosa-associated microbiota of intestinal pinch biopsies from 15 ileal CD patients with mild and moderate disease and from 58 healthy controls were analysed by 16S ribosomal sequencing to determine microbial profile differences between (1) IL23R, NOD2 and ATG16L1 genotypes in healthy subjects, (2) ileal CD patients and control subjects, and (3) inflamed and non-inflamed mucosal tissue in CD patients...
November 16, 2018: Journal of Crohn's & Colitis
Jinjin Cai, Karla M Pires, Maroua Ferhat, Bhagirath Chaurasia, Márcio A Buffolo, Rana Smalling, Ashot Sargsyan, Donald L Atkinson, Scott A Summers, Timothy E Graham, Sihem Boudina
Autophagy is a homeostatic cellular process involved in the degradation of long-lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity...
November 13, 2018: Cell Reports
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