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Fibroblast autophagy

Clémence Taisne, Marion Lussignol, Eva Hernandez, Arnaud Moris, Lina Mouna, Audrey Esclatine
During its life cycle, Human cytomegalovirus (HCMV) tightly modulates autophagy, a vesicular pathway allowing degradation and recycling of cellular components. To study the interplay between autophagy and the viral life cycle, we established various autophagy-deficient human fibroblastic cell lines. By knocking down the expression or activity of five autophagy-related proteins, we confirmed the proviral function that the autophagic machinery exerts on HCMV production. Using 3D reconstruction from confocal microscopy and electron microscopy, we demonstrated that lipidated LC3-positive vesicles accumulated at the viral assembly compartment (vAC)...
March 14, 2019: Scientific Reports
Hiroko Yanagisawa, Mohammad Arif Hossain, Takashi Miyajima, Kazuaki Nagao, Toshiyuki Miyashita, Yoshikatsu Eto
Lysosomes are an essential organ for cellular metabolism and play an important role in autophagy. We examined the association between methylation and autophagy in a severely affected female patient with Fabry disease, which is caused by mutation of the GLA gene on the X chromosome, and her two sisters, who had few symptoms. We confirmed autophagic flux by LC3 turnover assay using fibroblasts from each sister. In the severe female patient, autophagic flux showed abnormal while her two sisters with few symptoms had normal autophagic flux, revealing the direct relationship between symptoms and autophagic flux...
March 7, 2019: Molecular Genetics and Metabolism
Evelyn S Vincow, Ruth E Thomas, Gennifer Merrihew, Nicholas J Shulman, Theo K Bammler, James W MacDonald, Michael J MacCoss, Leo J Pallanck
The destruction of mitochondria through macroautophagy/autophagy has been recognized as a major route of mitochondrial protein degradation since its discovery more than fifty years ago, but fundamental questions remain unanswered. First, how much mitochondrial protein turnover occurs through autophagy? Mitochondrial proteins are also degraded by nonautophagic mechanisms, and the proportion of mitochondrial protein turnover that occurs through autophagy is still unknown. Second, does autophagy degrade mitochondrial proteins uniformly or selectively? Autophagy was originally thought to degrade all mitochondrial proteins at the same rate, but recent work suggests that mitochondrial autophagy may be protein selective...
March 13, 2019: Autophagy
Karolina Pierzynowska, Lidia Gaffke, Zuzanna Cyske, Grzegorz Węgrzyn
Mutations in the HTT gene, consisting of expansion of CAG triplets, cause the Huntington's disease (HD), one of the major neurodegenerative disorders. Formation of aggregates of mutant huntingtin (mHTT, the product of the mutant HTT gene) leads to cellular dysfunctions, and subsequent neurodegeneration which manifest clinically as motor abnormalities and cognitive deficits. We recently used immortalized HEK-293 cells expressing the 1st exon of the mutant HTT gene as a cellular model of HD, and showed that the stimulation of autophagy by genistein corrected the mutant phenotype...
March 9, 2019: Metabolic Brain Disease
Daniela Stanga, Qingchuan Zhao, Miroslav P Milev, Djenann Saint-Dic, Cecilia Jimenez-Mallebrera, Michael Sacher
TRAPPC11 has been implicated in membrane traffic and lipid-linked oligosaccharide synthesis, and mutations in TRAPPC11 result in neuromuscular and developmental phenotypes. Here, we show that TRAPPC11 has a role upstream of autophagosome formation during macroautophagy. Upon TRAPPC11 depletion, LC3-positive membranes accumulate prior to, and fail to be cleared during, starvation. A proximity biotinylation assay identified ATG2B and its binding partner WIPI4/WDR45 as TRAPPC11 interactors. TRAPPC11 depletion phenocopies that of ATG2 and WIPI4 and recruitment of both proteins to membranes is defective upon reduction of TRAPPC11...
March 7, 2019: Traffic
Cong Ma, Bo Wen, Qin Zhang, Pei-Pei Shao, Wen Gu, Kun Qu, Yang Shi, Bei Wang
Background: Ankylosing spondylitis (AS) is a type of rheumatoid disease, which has been reported to be associated with the excessive proliferation of fibroblasts recently. Emodin, a single component from a traditional Chinese medicine Rheum palmatum , exerts anti-inflammation and antirheumatic arthritis activities. However, could emodin be used to treat AS remains unclear? Thus, this study aimed to investigate the effect of emodin on AS. Methods: Fibroblasts obtained from patients with AS were used in the current study...
2019: Drug Design, Development and Therapy
Yasukazu Takanezawa, Ryosuke Nakamura, Yuka Sone, Shimpei Uraguchi, Masako Kiyono
Methylmercury (MeHg) is a highly toxic pollutant, and is considered hazardous to human health. In our previous study, we found that MeHg induces autophagy and that Atg5-dependent autophagy plays a protective role against MeHg toxicity. To further characterize the role of autophagy in MeHg-induced toxicity, we examined the impact of autophagy on microtubules and nuclei under MeHg exposure using Atg5KO mouse embryonic fibroblasts (MEFs). Low concentrations of MeHg induced a decrease in α-tubulin and acetylated-tubulin in both wild-type and Atg5KO cells...
February 20, 2019: Biochemical and Biophysical Research Communications
Jinzhong Zhang, Jing He, Jennifer L Johnson, Farhana Rahman, Evripidis Gavathiotis, Ana Maria Cuervo, Sergio D Catz
Cystinosis is a lysosomal storage disorder caused by defects in CTNS , the gene that encodes the lysosomal cystine transporter cystinosin. Patients with nephropathic cystinosis are characterized by endocrine defects, defective proximal tubule cell (PTC) function, the development of Fanconi syndrome and, eventually, end-stage renal disease. Kidney disease is developed despite the use of cysteamine, a drug that decreases lysosomal cystine overload but fails to correct overload-independent defects. Chaperone-mediated autophagy (CMA), a selective form of autophagy, is defective in cystinotic mouse fibroblasts, and treatment with cysteamine is unable to correct CMA defects in vivo , but whether the vesicular trafficking mechanisms that lead to defective CMA in cystinosis are manifested in human PTCs is not currently known and whether PTC-specific mechanisms are corrected upon CMA upregulation remains to be elucidated...
2019: Frontiers in Endocrinology
Satabdi Datta, Diptiman Choudhury, Amlan Das, Dipanwita Das Mukherjee, Moumita Dasgupta, Shreya Bandopadhyay, Gopal Chakrabarti
Paclitaxel is one of the most commonly used drugs for the treatment of nonsmall cell lung cancer (NSCLC). However acquired resistance to paclitaxel, epithelial to mesenchymal transition and cancer stem cell formation are the major obstacles for successful chemotherapy with this drug. Some of the major reasons behind chemoresistance development include increased ability of the cancer cells to survive under stress conditions by autophagy, increased expression of drug efflux pumps, tubulin mutations etc. In this study we found that inhibition of autophagy with chloroquine prevented development of paclitaxel resistance in A549 cells with time and potentiated the effect of paclitaxel by increased accumulation of superoxide-producing damaged mitochondria, with elevated ROS generation, it also increased the apoptotic rate and sub G0/ G1 phase arrest with time in A549 cells treated with paclitaxel and attenuated the metastatic potential and cancer stem cell population of the paclitaxel-resistant cells by ROS mediated modulation of the Wnt/β-catenin signaling pathway, thereby increasing paclitaxel sensitivity...
February 14, 2019: Apoptosis: An International Journal on Programmed Cell Death
Ramkumar Mathur, Mahabub Maraj Alam, Xiao-Feng Zhao, Yuan Liao, Jeffrey Shen, Shannon Morgan, Tingting Huang, HwaJeong Lee, Edward Lee, Yunfei Huang, Xinjun Zhu
Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn's disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL)-23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model...
February 14, 2019: Mucosal Immunology
Tingting Xie, Qiaoyi Xu, Hanxi Wan, Shunpeng Xing, Chen Shang, Yuan Gao, Zhengyu He
Pulmonary fibrosis is a major cause of death in patients with acute respiratory distress syndrome (ARDS). Our previous study revealed that lipopolysaccharide (LPS) challenge could lead to mouse lung fibroblast proliferation. Additionally, inhibition of autophagy in lung fibroblasts was also reported to be crucial during the process of pulmonary fibrosis. However, the correlation between proliferation and inhibition of autophagy of lung fibroblasts and the underlying mechanism remain unknown. In this study, we report that autophagy was inhibited in mouse lung fibroblasts after LPS challenge, and was accompanied by activation of the PI3K-Akt-mTOR signaling pathway...
February 13, 2019: Laboratory Investigation; a Journal of Technical Methods and Pathology
Yin-Lai Wang, Chi-Ting Horng, Min-Tsang Hsieh, Hung-Che Chen, Yu-Syuan Huang, Jai-Sing Yang, Guo-Kai Wang, Jo-Hua Chiang, Hul-Han Chen, Chi-Cheng Lu, Fu-An Chen
Polygonum cuspidatum (Hu Zhang) is a traditional Chinese medicine (TCM) and has been revealed to exert anticancer, anti‑angiogenesis, anti‑human immunodeficiency virus (HIV), anti‑hepatitis B virus, anti‑microbial, anti‑inflammatory, and neuro‑protective bio‑activities. However, the effect of P. cuspidatum extract (PCE) on drug‑resistant human oral cancer cells regarding cell death is not fully understood yet. The present study was undertaken to explore the induction of autophagic and apoptotic cell death and to investigate their underlying molecular mechanisms in PCE‑treated cisplatin‑resistant human oral cancer CAR cells...
January 28, 2019: Oncology Reports
Nicola Chiarelli, Giulia Carini, Nicoletta Zoppi, Marco Ritelli, Marina Colombi
Classical Ehlers-Danlos syndrome (cEDS) is a dominant inherited connective tissue disorder mainly caused by mutations in the COL5A1 and COL5A2 genes encoding type V collagen (COLLV), which is a fibrillar COLL widely distributed in a variety of connective tissues. cEDS patients suffer from skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. Most of the causative variants result in a non-functional COL5A1 allele and COLLV haploinsufficiency, whilst COL5A2 mutations affect its structural integrity...
2019: PloS One
Atsushi Tamura
Recently, the application of β-cyclodextrins (β-CDs) as therapeutic agents has received considerable attention. β-CDs have been reported to have therapeutic effects on various diseases, such as Niemann-Pick type C (NPC) disease, a family of lysosomal storage disorders characterized by the lysosomal accumulation of cholesterol. To further improve the therapeutic efficacy of β-CDs, the use of β-CD-threaded polyrotaxanes (PRXs) has been proposed as a carrier of β-CDs for NPC disease. PRXs are supramolecular polymers composed of many CDs threaded onto a linear polymer chain and capped with bulky stopper molecules...
2019: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Daniel Frank, David L Vaux, James M Murphy, James E Vince, Lisa M Lindqvist
Necroptosis is an inflammatory form of programmed cell death mediated by the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Upon phosphorylation by receptor-interacting protein kinase-3 (RIPK3), MLKL oligomerizes, and translocates to and disrupts the plasma membrane, thereby causing necroptotic cell lysis. Herein, we show that activation of necroptosis in mouse dermal fibroblasts (MDFs) and HT-29 human colorectal cancer cells results in accumulation of the autophagic marker, lipidated LC3B, in an MLKL-dependent manner...
February 1, 2019: Journal of Cell Science
Mark J Ranek, Kristen M Kokkonen-Simon, Anna Chen, Brittany L Dunkerly-Eyring, Miguel Pinilla Vera, Christian U Oeing, Chirag H Patel, Taishi Nakamura, Guangshuo Zhu, Djahida Bedja, Masayuki Sasaki, Ronald J Holewinski, Jennifer E Van Eyk, Jonathan D Powell, Dong Ik Lee, David A Kass
The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy1 . Its hyperactivation contributes to disease in numerous organs, including the heart1,2 , although broad inhibition of mTORC1 risks interference with its homeostatic roles. Tuberin (TSC2) is a GTPase-activating protein and prominent intrinsic regulator of mTORC1 that acts through modulation of RHEB (Ras homologue enriched in brain). TSC2 constitutively inhibits mTORC1; however, this activity is modified by phosphorylation from multiple signalling kinases that in turn inhibits (AMPK and GSK-3β) or stimulates (AKT, ERK and RSK-1) mTORC1 activity3-9 ...
January 30, 2019: Nature
M Vomero, V Manganelli, C Barbati, T Colasanti, A Capozzi, A Finucci, F R Spinelli, F Ceccarelli, C Perricone, S Truglia, S Morrone, R Maggio, R Misasi, M Bombardieri, M Di Franco, F Conti, M Sorice, G Valesini, C Alessandri
BACKGROUND: Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate...
January 29, 2019: Arthritis Research & Therapy
Seok Jeong Yoon, Chae Jin Lim, Hwa-Jee Chung, Joo-Hwan Kim, Yang Hoon Huh, Keedon Park, Sekyoo Jeong
Pollution-induced skin damage results in oxidative stress; cellular toxicity; inflammation; and, ultimately, premature skin aging. Previous studies suggest that the activation of autophagy can protect oxidation-induced cellular damage and aging-like changes in skin. In order to develop new anti-pollution ingredients, this study screened various kinds of natural extracts to measure their autophagy activation efficacy in cultured dermal fibroblast. The stimulation of autophagy flux by the selected extracts was further confirmed both by the expression of proteins associated with the autophagy signals and by electron microscope...
January 26, 2019: International Journal of Molecular Sciences
Xing Feng, Yanyan Jia, Yuyu Zhang, Fei Ma, Yuekun Zhu, Xuehui Hong, Qingxin Zhou, Ruixing He, Heng Zhang, Junfei Jin, Daxun Piao, He Huang, Qinghua Li, Xingfeng Qiu, Zhiyong Zhang
UVRAG (UV radiation resistance associated) is an important regulator of mammalian macroautophagy/autophagy by interacting with BECN1, PIK3C3, and RUBCN. Phosphorylation of UVRAG by MTORC1 negatively regulates autophagosome maturation under nutrient-enriched conditions. However, how UVRAG ubiquitination is regulated is still unknown. Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux...
January 27, 2019: Autophagy
Wang-Sheng Wang, Wen-Jiao Li, Ya-Wei Wang, Lu-Yao Wang, Ya-Bing Mi, Jiang-Wen Lu, Yi Lu, Chu-Yue Zhang, Kang Sun
The de novo synthesis of serum amyloid A1 (SAA1) is augmented in human fetal membranes at parturition. However, its role in parturitionremains largely unknown. Here, we investigated whether SAA1 wasinvolved inthe rupture of fetal membranes, a crucial event in parturition accompanied with extensive degradation of collagens. Results showed that SAA1 decreased both intracellular and extracellular COL1A1 and COL1A2 abundance,the two subunits ofcollagen I, without affecting theirmRNAlevels in human amnion fibroblasts...
January 25, 2019: Clinical Science (1979-)
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