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Virginie Hubert, Andrea Peschel, Brigitte Langer, Marion Gröger, Andrew Rees, Renate Kain
Autophagy is an evolutionarily conserved process used for removing surplus and damaged proteins and organelles from the cytoplasm. The unwanted material is incorporated into autophagosomes that eventually fuse with lysosomes, leading to the degradation of their cargo. The fusion event is mediated by the interaction between the Qa-SNARE syntaxin-17 (STX17) on autophagosomes and the R-SNARE VAMP8 on lysosomes. Cells deficient in lysosome membrane-associated protein-2 (LAMP-2) have increased numbers of autophagosomes but the underlying mechanism is poorly understood...
October 15, 2016: Biology Open
Zheng Wang, Guangyan Miao, Xue Xue, Xiangyang Guo, Chongzhen Yuan, Zhaoyu Wang, Gangming Zhang, Yingyu Chen, Du Feng, Junjie Hu, Hong Zhang
Mutations in the human autophagy gene EPG5 cause the multisystem disorder Vici syndrome. Here we demonstrated that EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG5 is recruited to late endosomes/lysosomes by direct interaction with Rab7 and the late endosomal/lysosomal R-SNARE VAMP7/8. EPG5 also binds to LC3/LGG-1 (mammalian and C. elegans Atg8 homolog, respectively) and to assembled STX17-SNAP29 Qabc SNARE complexes on autophagosomes. EPG5 stabilizes and facilitates the assembly of STX17-SNAP29-VAMP7/8 trans-SNARE complexes, and promotes STX17-SNAP29-VAMP7-mediated fusion of reconstituted proteoliposomes...
September 1, 2016: Molecular Cell
Ji-Yoon Choi, Nam-Hee Won, Jung-Duck Park, Sinae Jang, Chi-Yong Eom, Yongseok Choi, Young In Park, Mi-Sook Dong
Ethylmercury (EtHg) is derived from the degradation of thimerosal, the most widely used organomercury compound. In this study, EtHg-induced toxicity and autophagy in the mouse kidney was observed and then the mechanism of toxicity was explored in vitro in HK-2 cells. Low doses of EtHg induced autophagy without causing any histopathological changes in mouse kidneys. However, mice treated with high doses of EtHg exhibited severe focal tubular cell necrosis of the proximal tubules with autophagy. EtHg dose-dependently increased the production of reactive oxygen species, reduced the mitochondrial membrane potential, activated the unfolded protein response, and increased cytosolic Ca(2+) levels in HK-2 cells...
August 10, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Jia Hu, Ge Li, Liujing Qu, Ning Li, Wei Liu, Dan Xia, Beiqi Hongdu, Xin Lin, Chentong Xu, Yaxin Lou, Qihua He, Dalong Ma, Yingyu Chen
The formation of the autophagosome is controlled by an orderly action of ATG proteins. However, how these proteins are recruited to autophagic membranes remain poorly clarified. In this study, we have provided a line of evidence confirming that EVA1A (eva-1 homolog A)/TMEM166 (transmembrane protein 166) is associated with autophagosomal membrane development. This notion is based on dotted EVA1A structures that colocalize with ZFYVE1, ATG9, LC3B, ATG16L1, ATG5, STX17, RAB7 and LAMP1, which represent different stages of the autophagic process...
August 4, 2016: Cell Death & Disease
K X Gao, N B Chen, W J Liu, R Li, X Y Lan, H Chen, C Z Lei, R H Dang
Gray horses are born colored, and they then gradually lose their hair pigmentation. Tremendous progress has been made in identifying the genes responsible for graying with age in horses in recent years. Results show that gray coat color in horses is caused by a 4.6-kb duplication in intron 6 of the syntaxin 17 gene (STX17), which constitutes a cis-acting-regulatory mutation. However, little is known about the gray phenotype in native Chinese horses. This study was conducted to explore the frequency distribution of the gray mutation in native Chinese horse breeds...
2015: Genetics and Molecular Research: GMR
Yuanli Zhen, Wei Li
The HOPS (homotypic fusion and protein sorting) complex functions in endocytic and autophagic pathways in both lower eukaryotes and mammalian cells through its involvement in fusion events between endosomes and lysosomes or autophagosomes and lysosomes. However, the differential molecular mechanisms underlying these fusion processes are largely unknown. Buff (bf) is a mouse mutant that carries an Asp251-to-Glu point mutation (D251E) in the VPS33A protein, a tethering protein and a core subunit of the HOPS complex...
2015: Autophagy
Lívia A S Carmo, Felipe F Dias, Kássia K Malta, Kátia B Amaral, Revital Shamri, Peter F Weller, Rossana C N Melo
BACKGROUND: SNARE members mediate membrane fusion during intracellular trafficking underlying innate and adaptive immune responses by different cells. However, little is known about the expression and function of these proteins in human eosinophils, cells involved in allergic, inflammatory and immunoregulatory responses. Here, we investigate the expression and distribution of the Qa-SNARE syntaxin17 (STX17) within human eosinophils isolated from the peripheral blood. METHODS: Flow cytometry and a pre-embedding immunonanogold electron microscopy (EM) technique that combines optimal epitope preservation and secondary Fab-fragments of antibodies linked to 1...
October 1, 2015: Experimental Cell Research
Rong Liu, Xiaoyong Zhi, Qing Zhong
Autophagosome fusion with a lysosome constitutes the last barrier for autophagic degradation. It is speculated that this fusion process is precisely and tightly regulated. Recent genetic evidence suggests that a set of SNARE proteins, including STX17, SNAP29, and VAMP8, are essential for the fusion between autophagosomes and lysosomes. However, it remains unclear whether these SNAREs are fusion competent and how their fusogenic activity is specifically regulated during autophagy. Using a combination of biochemical, cell biology, and genetic approaches, we demonstrated that fusogenic activity of the autophagic SNARE complex is temporally and spatially controlled by ATG14/Barkor/Atg14L, an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex (PtdIns3K)...
2015: Autophagy
Amélie Bernard, Daniel J Klionsky
Although largely overlooked relative to the process of phagophore formation, the mechanism through which autophagosomes fuse with lysosomes is a critical aspect of macroautophagy that is not fully understood. In particular, this step must be carefully regulated to prevent premature fusion of an incomplete autophagosome (that is, a phagophore) with a lysosome, because such an event would not allow access of the partially sequestered cargo to the lysosome lumen. The identification of the autophagosome-associated SNARE protein STX17 (syntaxin 17) provided some clue in the understanding of this process...
April 3, 2015: Autophagy
Jiajie Diao, Rong Liu, Yueguang Rong, Minglei Zhao, Jing Zhang, Ying Lai, Qiangjun Zhou, Livia M Wilz, Jianxu Li, Sandro Vivona, Richard A Pfuetzner, Axel T Brunger, Qing Zhong
Autophagy, an important catabolic pathway implicated in a broad spectrum of human diseases, begins by forming double membrane autophagosomes that engulf cytosolic cargo and ends by fusing autophagosomes with lysosomes for degradation. Membrane fusion activity is required for early biogenesis of autophagosomes and late degradation in lysosomes. However, the key regulatory mechanisms of autophagic membrane tethering and fusion remain largely unknown. Here we report that ATG14 (also known as beclin-1-associated autophagy-related key regulator (Barkor) or ATG14L), an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex, promotes membrane tethering of protein-free liposomes, and enhances hemifusion and full fusion of proteoliposomes reconstituted with the target (t)-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) syntaxin 17 (STX17) and SNAP29, and the vesicle (v)-SNARE VAMP8 (vesicle-associated membrane protein 8)...
April 23, 2015: Nature
Lin Jiang, Cécile Campagne, Elisabeth Sundström, Pedro Sousa, Saima Imran, Monika Seltenhammer, Gerli Pielberg, Mats J Olsson, Giorgia Egidy, Leif Andersson, Anna Golovko
BACKGROUND: Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses...
2014: BMC Cancer
Yuanyuan Chen, Delong Meng, Huibo Wang, Ruochuan Sun, Dongrui Wang, Shuai Wang, Jiajun Fan, Yingjie Zhao, Jingkun Wang, Song Yang, Cong Huai, Xiao Song, Rong Qin, Tao Xu, Dapeng Yun, Lingna Hu, Jingmin Yang, Xiaotian Zhang, Haoming Chen, Juxiang Chen, Hongyan Chen, Daru Lu
BACKGROUND: Malignant glioma is a common and lethal primary brain tumor in adults. Here we identified a novel oncoprotein, vesicle-associated membrane protein 8 (VAMP8), and investigated its roles in tumorigenisis and chemoresistance in glioma. METHODS: The expression of gene and protein were determined by quantitative PCR and Western blot, respectively. Histological analysis of 282 glioma samples and 12 normal controls was performed by Pearson's chi-squared test...
March 2015: Neuro-oncology
Mathias Faure
Autophagy, a vesicular pathway involving the lysosomal degradation of cytosolic contents, is frequently hijacked by intracellular pathogens to optimize their infectivity. In this issue of Cell Host & Microbe, Ding et al. (2014) show that human parainfluenza virus exploits autophagy by targeting SNAREs and preventing the SNAP29-Stx17 interaction, an otherwise crucial event in autophagosome-lysosome fusion.
May 14, 2014: Cell Host & Microbe
Peidu Jiang, Taki Nishimura, Yuriko Sakamaki, Eisuke Itakura, Tomohisa Hatta, Tohru Natsume, Noboru Mizushima
Membrane fusion is generally controlled by Rabs, soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), and tethering complexes. Syntaxin 17 (STX17) was recently identified as the autophagosomal SNARE required for autophagosome-lysosome fusion in mammals and Drosophila. In this study, to better understand the mechanism of autophagosome-lysosome fusion, we searched for STX17-interacting proteins. Immunoprecipitation and mass spectrometry analysis identified vacuolar protein sorting 33A (VPS33A) and VPS16, which are components of the homotypic fusion and protein sorting (HOPS)-tethering complex...
April 2014: Molecular Biology of the Cell
Krisztina Hegedűs, Szabolcs Takáts, Attila L Kovács, Gábor Juhász
Phagophores engulf cytoplasmic material and give rise to autophagosomes, double-membrane vesicles mediating cargo transport to lysosomes for degradation. The regulation of autophagosome fusion with endosomes and lysosomes during autophagy has remained poorly characterized. Two recent papers conclude that STX17/syntaxin 17 (Syx17 in Drosophila) has an evolutionarily conserved role in autophagosome fusion with endosomes and lysosomes, acting in one SNARE complex with SNAP29 (ubisnap in Drosophila) and the endosomal/lysosomal VAMP8 (CG1599/Vamp7 in Drosophila)...
October 2013: Autophagy
R B C Teixeira, A K Rendahl, S M Anderson, J R Mickelson, D Sigler, B R Buchanan, R J Coleman, M E McCue
BACKGROUND: Both graying and melanoma formation in horses have recently been linked to a duplication in the STX17 gene. This duplication, as well as a mutation in the ASIP gene that increases MC1R pathway signaling, affects melanoma risk and severity in gray horses. OBJECTIVE: To determine if melanoma susceptibility in gray Quarter Horses (QH) is lower than gray horses from other breeds because of decreased MC1R signaling resulting from a high incidence of the MC1R chestnut coat color allele in the QH population...
September 2013: Journal of Veterinary Internal Medicine
Eisuke Itakura, Noboru Mizushima
The phagophore (also called isolation membrane) elongates and encloses a portion of cytoplasm, resulting in formation of the autophagosome. After completion of autophagosome formation, the outer autophagosomal membrane becomes ready to fuse with the lysosome for degradation of enclosed cytoplasmic materials. However, the molecular mechanism for how the fusion of completed autophagosomes with the lysosome is regulated has not been fully understood. We discovered syntaxin 17 (STX17) as an autophagosomal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)...
June 1, 2013: Autophagy
Maho Hamasaki, Nobumichi Furuta, Atsushi Matsuda, Akiko Nezu, Akitsugu Yamamoto, Naonobu Fujita, Hiroko Oomori, Takeshi Noda, Tokuko Haraguchi, Yasushi Hiraoka, Atsuo Amano, Tamotsu Yoshimori
Autophagy is a tightly regulated intracellular bulk degradation/recycling system that has fundamental roles in cellular homeostasis. Autophagy is initiated by isolation membranes, which form and elongate as they engulf portions of the cytoplasm and organelles. Eventually isolation membranes close to form double membrane-bound autophagosomes and fuse with lysosomes to degrade their contents. The physiological role of autophagy has been determined since its discovery, but the origin of autophagosomal membranes has remained unclear...
March 21, 2013: Nature
Ino Curik, Thomas Druml, Monika Seltenhammer, Elisabeth Sundström, Gerli Rosengren Pielberg, Leif Andersson, Johann Sölkner
The dominant phenotype of greying with age in horses, caused by a 4.6-kb duplication in intron 6 of STX17, is associated with a high incidence of melanoma and vitiligo-like skin depigmentation. However, the progressive greying and the incidence of melanoma, vitiligo-like depigmentation, and amount of speckling in these horses do not follow a simple inheritance pattern. To understand their inheritance, we analysed the melanoma grade, grey level, vitiligo grade, and speckling grade of 1,119 Grey horses (7,146 measurements) measured in six countries over a 9-year period...
2013: PLoS Genetics
Justin A McDonough, Hayley J Newton, Scott Klum, Rachel Swiss, Hervé Agaisse, Craig R Roy
UNLABELLED: Coxiella burnetii is an intracellular pathogen that replicates within a lysosome-like vacuole. A Dot/Icm type IVB secretion system is used by C. burnetii to translocate effector proteins into the host cytosol that likely modulate host factor function. To identify host determinants required for C. burnetii intracellular growth, a genome-wide screen was performed using gene silencing by small interfering RNA (siRNA). Replication of C. burnetii was measured by immunofluorescence microscopy in siRNA-transfected HeLa cells...
2013: MBio
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