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Caihong Wang, Kyle A Bauckman, Adam S B Ross, Jane W Symington, Marianne M Ligon, Gael Scholtes, Akhil Kumar, Hao-Wei Chang, Joy Twentyman, Bisiayo E Fashemi, Ramnik J Xavier, Indira U Mysorekar
50% of Caucasians carry a Thr300Ala variant (T300A) in the protein encoded by the macroautophagy/autophagy gene ATG16L1. Here, we show that the T300A variant confers protection against urinary tract infections (UTIs), the most common infectious disease in women. Using knockin mice carrying the human T300A variant, we show that the variant limits the UTI-causing bacteria, uropathogenic Escherichia coli (UPEC), from establishing persistent intracellular reservoirs, which can seed UTI recurrence. This phenotype is recapitulated in mice lacking Atg16l1 or Atg7 exclusively in the urothelium...
October 18, 2018: Autophagy
Haijin Huang, Jie Tang, Lei Zhang, Yanzhi Bu, Xiaoyu Zhang
Chemotherapy is an important treatment option for gastric cancer (GC); however, chemotherapy usually fails due to drug resistance, particularly multidrug resistance (MDR). In our previous studies, microRNA (miR)‑874 was demonstrated to serve an important role in tumour growth, apoptosis and angiogenesis. In the present study, the precise roles and underlying mechanisms of miR‑874 in MDR were investigated in GC. The overexpression of miR‑874 reversed cancer cell drug resistance in vitro. According to reporter gene and western blot assays, Autophagy‑related 16‑like 1 (ATG16 L1) was identified as a direct target of miR‑874...
October 11, 2018: International Journal of Oncology
Kalaiselvi Palanisamy, Tsung-Hsun Tsai, Tung-Min Yu, Kuo-Ting Sun, Shao-Hua Yu, Feng-Yen Lin, I-Kuan Wang, Chi-Yuan Li
Autophagy, a prosurvival mechanism offers a protective role during acute kidney injury. We show novel findings on the functional role of RNA binding protein, HuR during hypoxia-induced autophagy in renal proximal tubular cells-2 (HK-2). HK-2 cells showed upregulated expressions of HuR and autophagy-related proteins such as autophagy related 7 (ATG7), autophagy related 16 like 1 (ATG16L1), and LC3II under hypoxia. Increased autophagosome formation was visualized as LC3 puncta in hypoxic cells. Further, short hairpin-RNA-mediated loss of HuR function in HK-2 cells significantly decreased ATG7 and ATG16L1 protein expressions...
October 14, 2018: Journal of Cellular Physiology
Guillaume Le Baut, Claire O'Brien, Paul Pavli, Maryline Roy, Philippe Seksik, Xavier Tréton, Stéphane Nancey, Nicolas Barnich, Madeleine Bezault, Claire Auzolle, Dominique Cazals-Hatem, Jérome Viala, Matthieu Allez, Jean-Pierre Hugot, Anne Dumay
Yersinia are common contaminants of food products, but their prevalence in the human gut is poorly documented. Yersinia have been implicated in Crohn's Disease (CD, an inflammatory bowel disease) however their role in CD is controversial. We performed highly sensitive PCR assays of specific sequences for the gyrB gene of Y. aldovae, Y. bercovieri, Y. enterocolitica, Y. intermedia, Y. mollaretii and the inv gene of Y. pseudotuberculosis . We analyzed a total of 470 ileal samples taken from 338 participants (262 CD patients and 76 controls) belonging to three independent cohorts...
2018: Frontiers in Cellular and Infection Microbiology
Ben C King, Klaudia Kulak, Ulrika Krus, Rebecca Rosberg, Ewelina Golec, Katarzyna Wozniak, Maria F Gomez, Enming Zhang, David J O'Connell, Erik Renström, Anna M Blom
We show here that human pancreatic islets highly express C3, which is both secreted and present in the cytosol. Within isolated human islets, C3 expression correlates with type 2 diabetes (T2D) donor status, HbA1c, and inflammation. Islet C3 expression is also upregulated in several rodent diabetes models. C3 interacts with ATG16L1, which is essential for autophagy. Autophagy relieves cellular stresses faced by β cells during T2D and maintains cellular homeostasis. C3 knockout in clonal β cells impaired autophagy and led to increased apoptosis after exposure of cells to palmitic acid and IAPP...
October 1, 2018: Cell Metabolism
Ahmed M Fahmy, Marwa Khabir, Matthieu Blanchet, Patrick Labonté
Hepatitis C virus (HCV) infection is known to induce autophagosome accumulation as observed by the typical punctate cytoplasmic distribution of LC3B-II in infected cells. Previously, we showed that viral RNA-dependent RNA polymerase (NS5B) interacts with ATG5, a major component of the autophagy elongation complex that is involved in the formation of double-membrane vesicles (DMV), and demonstrated that the autophagy elongation complex (ATG5-12/16L1) but not LC3B is required for proper membranous web formation...
2018: PloS One
Matteo Santoni, Francesco Piva, Ugo De Giorgi, Alessandra Mosca, Umberto Basso, Daniele Santini, Sebastiano Buti, Cristian Lolli, Carlo Terrone, Marco Maruzzo, Michele Iuliani, Melissa Bersanelli, Alessandro Conti, Roberta Mazzucchelli, Rodolfo Montironi, Luciano Burattini, Rossana Berardi
BACKGROUND/AIM: Autophagy has been shown to be involved in cancer development and response to cancer therapy. In this study, genotypes of autophagic genes were analyzed to assess their correlation with the risk of clear cell renal cell carcinoma (ccRCC) and the outcome of patients treated with pazopanib for metastatic ccRCC. MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs)were selected in the following genes: ATG4A (rs7880351), ATG4B (rs6709768), ATG4C (rs2886770, rs6670694, rs6683832), ATG5 (rs9373839, rs3804333, rs490010), ATG16L1 (rs6752107), ATG16L2 (rs10751215) and IRGM (rs10059011)...
October 2018: Anticancer Research
Shay Ben-Shachar, Yael Finezilber, Hofit Elad, Keren Rabinowitz, Idan Goren, Ofer Isakov, Henit Yanai, Iris Dotan
Background: We evaluated the impact of variations in ATG16L1 and NOD2 and genes on serologic responses in patients with inflammatory bowel disease (IBD). Methods: We recruited 308 IBD patients: 130 with Crohn's disease (CD), 67 with ulcerative colitis (UC), 111 with UC and an ileal pouch (UC-pouch), and 74 healthy controls. NOD2 variants (1007fs, G908R, R702W) and the ATG16L1 A300T variant were analyzed. The antiglycan antibodies anti-Saccharomyces cerevisiae (ASCA), antilaminaribioside (ALCA), antichitobioside (ACCA), and antimannobioside carbohydrate (AMCA) were analyzed by enzyme-linked immunosorbent assay...
September 27, 2018: Inflammatory Bowel Diseases
Songül Budak Diler, Fatma Aybuğa
Background: Urological cancers (prostate cancer and bladder cancers) are the most common cancers in Western population and its rate is increasing in the Eastern World. Autophagy has appeared as a fundamental repair mechanism for degrading damaged organelles and proteins. It was clear that autophagy gene polymorphisms are correlated with development of inflammatory bowel disease and it can also be related with prostate cancer (PCa) or bladder cancer (BCa). In this study, we aimed to determine if ATG16L1 (Thr300Ala) polymorphism is associated with an increased risk of developing PCa and BCa and to establish correlations between ATG16L1 genotypes and morphological parameters...
September 26, 2018: Asian Pacific Journal of Cancer Prevention: APJCP
Konrad Aden, Florian Tran, Go Ito, Raheleh Sheibani-Tezerji, Simone Lipinski, Jan W Kuiper, Markus Tschurtschenthaler, Svetlana Saveljeva, Joya Bhattacharyya, Robert Häsler, Kareen Bartsch, Anne Luzius, Marlene Jentzsch, Maren Falk-Paulsen, Stephanie T Stengel, Lina Welz, Robin Schwarzer, Björn Rabe, Winfried Barchet, Stefan Krautwald, Gunther Hartmann, Manolis Pasparakis, Richard S Blumberg, Stefan Schreiber, Arthur Kaser, Philip Rosenstiel
A coding variant of the inflammatory bowel disease (IBD) risk gene ATG16L1 has been associated with defective autophagy and deregulation of endoplasmic reticulum (ER) function. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. We show that ATG16L1 critically orchestrates IL-22 signaling in the intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress and subsequent activation of STING-dependent type I interferon (IFN-I) signaling, which is augmented in Atg16l1 ΔIEC intestinal organoids...
September 25, 2018: Journal of Experimental Medicine
Huishan Guo, Remy Sadoul, Derrick Gibbings
Autophagy-related-5 (Atg5) and Autophagy-related-16-Like-1 (Atg16L1) canonically participate in autophagy. Recent research demonstrates that apart from this, they also control production of extracellular vesicles called exosomes by regulating acidification of late endosomes. Atg5-mediated exosome production increased migration and metastasis of breast cancer cells suggesting exosomes may perform some functions ascribed to autophagy.
2018: Molecular & Cellular Oncology
He Liu, Zhaoyue He, Peter Bode, Holger Moch, Hans-Uwe Simon
Autophagy is a cellular "self-digestion" process known to be essential for various physiological and pathological pathways, including cancer, where its role appears to be context-dependent. In this work, we aimed to investigate the level of autophagy by evaluating the expression of key autophagy-related proteins (ATGs) in testicular germ cell tumors (TGCT) for which autophagy has been rarely investigated. We decided to use an immunohistochemical (IHC) staining approach employing a tissue microarray (TMA)...
2018: Frontiers in Oncology
Claudio Lera Orsatti, Marcone Lima Sobreira, Valéria Cristina Sandrim, Jorge Nahas-Neto, Fabio Lera Orsatti, Eliana Aguiar Petri Nahas
BACKGROUND: Early identification of asymptomatic postmenopausal women (PW), who are more predisposed to developing cardiovascular disease (CVD), is an important preventive strategy. Autophagy-related 16-like 1 (ATG16L1) is an autophagy gene known to control host immune responses and is associated with a variety of diseases, including CVD. OBJECTIVE: The aim of the study was to associate the ATG16L1 polymorphism variant with subclinical carotid atherosclerosis in asymptomatic PW...
September 17, 2018: Clinical Biochemistry
Yan Li, Dongmei Zhou, Yinghui Ren, Zimu Zhang, Xiangdong Guo, MingKun Ma, Zhenyi Xue, Jienv Lv, Hongkun Liu, Qing Xi, Long Jia, Lijuan Zhang, Ying Liu, Qi Zhang, Jun Yan, Yurong Da, Fei Gao, Jianbo Yue, Zhi Yao, Rongxin Zhang
Microglia are innate immune cells in the central nervous system (CNS), that supplies neurons with key factors for executing autophagosomal/lysosomal functions. Macroautophagy/autophagy is a cellular catabolic process that maintains cell balance in response to stress-related stimulation. Abnormal autophagy occurs with many pathologies, such as cancer, and autoimmune and neurodegenerative diseases. Hence, clarification of the mechanisms of autophagy regulation is of utmost importance. Recently, researchers presented microRNAs (miRNAs) as novel and potent modulators of autophagic activity...
September 13, 2018: Autophagy
Florent Arbogast, Johan Arnold, Philippe Hammann, Lauriane Kuhn, Johana Chicher, Diane Murera, Justine Weishaar, Sylviane Muller, Jean-Daniel Fauny, Frédéric Gros
The involvement of macroautophagy/autophagy proteins in B-cell receptor (BCR) trafficking, although suspected, is not well understood. We show that ATG5 (autophagy related 5) contributes to BCR polarization after stimulation and internalization into LAMP1 (lysosomal-associated membrane protein 1)+ and major histocompatibility complex class II (MHC-II)+ compartments. BCR polarization is crucial in the context of immobilized antigen processing. Moreover, antigen presentation to cognate T cells is decreased in the absence of ATG5 when the model antigen OVAL/ovalbumin is provided in an immobilized form in contrast to the normal presentation of soluble OVAL...
September 22, 2018: Autophagy
Kautilya Kumar Jena, Srinivasa Prasad Kolapalli, Subhash Mehto, Parej Nath, Biswajit Das, Pradyumna Kumar Sahoo, Abdul Ahad, Gulam Hussain Syed, Sunil K Raghav, Shantibhusan Senapati, Swati Chauhan, Santosh Chauhan
Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress-induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62-NRF2 axis. We show that TRIM16 is an integral part of the p62-KEAP1-NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2...
September 14, 2018: EMBO Journal
Ta-Chiang Liu, Justin T Kern, Kelli L VanDussen, Shanshan Xiong, Gerard E Kaiko, Craig B Wilen, Michael W Rajala, Roberta Caruso, Michael J Holtzman, Feng Gao, Dermot Pb McGovern, Gabriel Nunez, Richard D Head, Thaddeus S Stappenbeck
It is suggested that subtyping of complex inflammatory diseases can be based on genetic susceptibility and relevant environmental exposure (G+E). We propose that using matched cellular phenotypes in human subjects and corresponding preclinical models with the same G+E combinations is useful to this end. As an example, defective Paneth cells can subtype Crohn's disease (CD) subjects; Paneth cell defects have been linked to multiple CD susceptibility genes and are associated with poor outcome. We hypothesized that CD susceptibility genes interact with cigarette smoking, a major CD environmental risk factor, to trigger Paneth cell defects...
August 23, 2018: Journal of Clinical Investigation
Yasuomi Urano, Chinatsu Mori, Ayano Fuji, Keito Konno, Takayuki Yamamoto, Shohei Yashirogi, Mayu Ando, Yoshiro Saito, Noriko Noguchi
PARK7/DJ-1 is a Parkinson disease- and cancer-associated protein that functions as a multifunctional protein involved in gene transcription regulation and anti-oxidative defense. Although PARK7 lacks the secretory signal sequence, it is secreted and plays important physiological and pathophysiological roles. Whereas secretory proteins that lack the endoplasmic reticulum-targeting signal sequence are secreted from cells by way of what is called the unconventional secretion mechanism, the specific processes responsible for causing PARK7 to be secreted across the plasma membrane have remained unclear...
2018: Autophagy
Megha Bansal, Shivranjani C Moharir, Ghanshyam Swarup
Autophagy is an essential physiological process that maintains cellular homeostasis by eliminating harmful protein aggregates, damaged organelles and certain pathogens through lysosomal degradation. During autophagy specialized structures, known as autophagosomes are formed that recruit the cargo through autophagy receptors, and deliver it to lysosomes. Optineurin (Optn) is an autophagy receptor that mediates cargo selective autophagy. Recently, we have identified a novel function of Optn that promotes autophagosome formation during non-selective autophagy...
2018: Communicative & Integrative Biology
Maureen E Hill, Anil Kumar, James A Wells, Tom C Hobman, Olivier Julien, Jeanne A Hardy
Zika virus is an emerging mosquito-borne pathogen capable of severely damaging developing fetuses as well as causing neurological abnormalities in adults. The molecular details of how Zika virus causes pathologies that are unique among the flavivirus family remain poorly understood and have contributed to the lack of Zika antiviral therapies. To elucidate how Zika virus protease (ZVP) affects host cellular pathways and consequent pathologies, we used unbiased N-terminomics to identify 31 human proteins cleaved by the NS2B-NS3 protease...
September 21, 2018: ACS Chemical Biology
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