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https://www.readbyqxmd.com/read/28424277/janus-kinase-2-regulates-transcription-factor-eb-expression-and-autophagy-completion-in-glomerular-podocytes
#1
Tamadher A Alghamdi, Syamantak Majumder, Karina Thieme, Sri N Batchu, Kathryn E White, Youan Liu, Angela S Brijmohan, Bridgit B Bowskill, Suzanne L Advani, Minna Woo, Andrew Advani
The nonreceptor kinase Janus kinase 2 (JAK2) has garnered attention as a promising therapeutic target for the treatment of CKD. However, being ubiquitously expressed in the adult, JAK2 is also likely to be necessary for normal organ function. Here, we investigated the phenotypic effects of JAK2 deficiency. Mice in which JAK2 had been deleted from podocytes exhibited an elevation in urine albumin excretion that was accompanied by increased podocyte autophagosome fractional volume and p62 aggregation, which are indicative of impaired autophagy completion...
April 19, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28416685/snat7-is-the-primary-lysosomal-glutamine-exporter-required-for-extracellular-protein-dependent-growth-of-cancer-cells
#2
Quentin Verdon, Marielle Boonen, Christopher Ribes, Michel Jadot, Bruno Gasnier, Corinne Sagné
Lysosomes degrade cellular components sequestered by autophagy or extracellular material internalized by endocytosis and phagocytosis. The macromolecule building blocks released by lysosomal hydrolysis are then exported to the cytosol by lysosomal transporters, which remain undercharacterized. In this study, we designed an in situ assay of lysosomal amino acid export based on the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis that detects lysosomal storage. This assay was used to screen candidate lysosomal transporters, leading to the identification of sodium-coupled neutral amino acid transporter 7 (SNAT7), encoded by the SLC38A7 gene, as a lysosomal transporter highly selective for glutamine and asparagine...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28408365/immunomodulators-targeting-marco-expression-improve-resistance-to-post-influenza-bacterial-pneumonia
#3
Muzo Wu, John G Gibbons, Glen M Deloid, Alice S Bedugnis, Rajesh K Thimmulappa, Shyam Biswal, Lester Kobzik
Down-regulation of the alveolar macrophage (AM) macrophage receptor with collagenous structure (MARCO) leads to susceptibility to post-influenza bacterial pneumonia, a major cause of morbidity and mortality. We sought to determine whether immunomodulation of MARCO could improve host defense and resistance to secondary bacterial pneumonia. RNAseq analysis identified a striking increase of MARCO expression between days 9 and 11 after influenza infection and indicated important roles for Akt and Nrf2 in MARCO recovery...
April 13, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28386045/naadp-mediated-ca-2-signaling-promotes-autophagy-and-protects-against-lps-induced-liver-injury
#4
So-Young Rah, Young-Hoon Lee, Uh-Hyun Kim
LPS has been shown to induce hepatocyte autophagy, but little is known about how LPS is able to do this during acute toxic liver injury. Our aim was to determine the existence of any selective Ca(2+) signaling coupling to hepatocyte autophagy in response to LPS. LPS increased the autophagic process in hepatocytes, and CD38 knockdown prevented this response. Ned19, a specific inhibitor for nicotinic acid adenine dinucleotide phosphate (NAADP), prevented LPS-mediated Ca(2+) signaling and autophagosome formation in hepatocytes...
April 6, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28374748/fasting-induced-hormonal-regulation-of-lysosomal-function
#5
Liqun Chen, Ke Wang, Aijun Long, Liangjie Jia, Yuanyuan Zhang, Haiteng Deng, Yu Li, Jinbo Han, Yiguo Wang
Lysosomes are centers for nutrient sensing and recycling that allow mammals to adapt to starvation. Regulation of lysosome dynamics by internal nutrient signaling is well described, but the mechanisms by which external cues modulate lysosomal function are unclear. Here, we describe an essential role of the fasting-induced hormone fibroblast growth factor 21 (FGF21) in lysosome homeostasis in mice. Fgf21 deficiency impairs hepatic lysosomal function by blocking transcription factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy...
April 4, 2017: Cell Research
https://www.readbyqxmd.com/read/28368693/galectins-and-trims-directly-interact-and-orchestrate-autophagic-response-to-endomembrane-damage
#6
Suresh Kumar, Santosh Chauhan, Ashish Jain, Marisa Ponpuak, Seong Won Choi, Michal Mudd, Ryan Peters, Michael A Mandell, Terje Johansen, Vojo Deretic
Macroautophagy/autophagy is a homeostatic process delivering cytoplasmic targets, including damaged organelles, to lysosomes for degradation; however, it is not completely understood how compromised endomembranes are recognized by the autophagic apparatus. We have described previously that the TRIM family of proteins act as receptors for selective autophagy. In this study we uncovered the property of TRIMs to directly interact with members of the family of cytosolic lectins termed galectins. Galectins patrol the cytoplasm and recognize compromised membranes...
April 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28366813/mita-modulated-autophagy-flux-promotes-cell-death-in-breast-cancer-cells
#7
Khyati Bhatelia, Kritarth Singh, Paresh Prajapati, Lakshmi Sripada, Milton Roy, Rajesh Singh
The crosstalk between inflammation and autophagy is an emerging phenomenon observed during tumorigenesis. Activation of NF-κB and IRF3 plays a key role in the regulation of cytokines that are involved in tumor growth and progression. The genes of innate immunity are known to regulate the master transcription factors like NF-κB and IRF3. Innate immunity pathways at the same time regulate the genes of the autophagy pathway which are essential for tumor cell metabolism. In the current study, we studied the role of MITA (Mediator of IRF3 Activation), a regulator of innate immunity, in the regulation of autophagy and its implication in cell death of breast cancer cells...
March 31, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28355222/transaldolase-inhibition-impairs-mitochondrial-respiration-and-induces-a-starvation-like-longevity-response-in-caenorhabditis-elegans
#8
Christopher F Bennett, Jane J Kwon, Christine Chen, Joshua Russell, Kathlyn Acosta, Nikolay Burnaevskiy, Matthew M Crane, Alessandro Bitto, Helen Vander Wende, Marissa Simko, Victor Pineda, Ryan Rossner, Brian M Wasko, Haeri Choi, Shiwen Chen, Shirley Park, Gholamali Jafari, Bryan Sands, Carissa Perez Olsen, Alexander R Mendenhall, Philip G Morgan, Matt Kaeberlein
Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28350209/b-cell-non-hodgkin-lymphoma-selective-vulnerability-to-pikfyve-inhibition
#9
Sophia Gayle, Sean Landrette, Neil Beeharry, Chris Conrad, Marylens Hernandez, Paul Beckett, Shawn M Ferguson, Tian Xu, Jonathan Rothberg, Henri Lichenstein
We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity...
March 28, 2017: Autophagy
https://www.readbyqxmd.com/read/28345620/acute-and-chronic-mitochondrial-respiratory-chain-deficiency-differentially-regulate-lysosomal-biogenesis
#10
Lorena Fernández-Mosquera, Cátia V Diogo, King Faisal Yambire, Gabriela L Santos, Marta Luna Sánchez, Paule Bénit, Pierre Rustin, Luis Carlos Lopez, Ira Milosevic, Nuno Raimundo
Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28338654/tfeb-vegfa-6p21-1-co-amplified-renal-cell-carcinoma-a-distinct-entity-with-potential-implications-for-clinical-management
#11
Sounak Gupta, Sarah H Johnson, George Vasmatzis, Binu Porath, Jeannette G Rustin, Priya Rao, Brian A Costello, Bradley C Leibovich, R Houston Thompson, John C Cheville, William R Sukov
A subset of renal cell carcinomas shows TFEB overexpression secondary to MALAT1-TFEB gene fusion. As alternate mechanisms of TFEB overexpression are likely to have the same effect, we sought to determine the frequency of amplification of TFEB and the adjacent VEGFA gene at 6p21.1. As patients with metastatic renal cell carcinomas are managed with anti-VEGF therapies, we retrospectively assessed therapeutic response in patients with amplified tumors. Amplification status was analyzed for 875 renal cell carcinomas from our institution, a consultative case and 794 cases from The Cancer Genome Atlas...
March 24, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28336683/let-7-regulates-radial-migration-of-new-born-neurons-through-positive-regulation-of-autophagy
#12
Rebecca Petri, Karolina Pircs, Marie E Jönsson, Malin Åkerblom, Per Ludvik Brattås, Thies Klussendorf, Johan Jakobsson
During adult neurogenesis, newly formed olfactory bulb (OB) interneurons migrate radially to integrate into specific layers of the OB Despite the importance of this process, the intracellular mechanisms that regulate radial migration remain poorly understood. Here, we find that microRNA (miRNA) let-7 regulates radial migration by modulating autophagy in new-born neurons. Using Argonaute2 immunoprecipitation, we performed global profiling of miRNAs in adult-born OB neurons and identified let-7 as a highly abundant miRNA family...
March 23, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28322484/tfe3-positive-renal-cell-carcinoma-occurring-in-three-children-with-dysfunctional-kidneys-on-immunosuppression
#13
Beverly A Schaefer, Theodore S Johnson, David K Hooper, Jaimie D Nathan, James I Geller
Pediatric RCC is a rare pediatric neoplasm and is distinctly different compared to adult RCC, often demonstrating translocation morphology evidenced by unique histopathological features and TFE3 or TFEB nuclear expression. We report three cases of pediatric TFE3 positive RCC (TFE3-RCC) occurring in the setting of chronic kidney disease and long-term pharmacological immunosuppression, including two cases that developed in the native kidney following kidney transplantation. Together, these cases suggest that the kidney microenvironment in combination with immune dysregulation is likely contributing factors in the pathogenesis of some pediatric RCC, warranting further study...
March 21, 2017: Pediatric Transplantation
https://www.readbyqxmd.com/read/28319438/systemic-deregulation-of-autophagy-upon-loss-of-als-and-ftd-linked-c9orf72
#14
Yon Ji, Janet Ugolino, Nathan Ryan Brady, Anne Hamacher-Brady, Jiou Wang
A genetic mutation in the C9orf72 gene causes the most common forms of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 protein, predicted to be a DENN-family protein, is reduced in ALS and FTD, but its functions remain poorly understood. Using a 3110043O21Rik/C9orf72 knockout mouse model, as well as cellular analysis, we have found that loss of C9orf72 causes alterations in the signaling states of central autophagy regulators. In particular, C9orf72 depletion leads to reduced activity of MTOR, a negative regulator of macroautophagy/autophagy, and concomitantly increased TFEB levels and nuclear translocation...
March 20, 2017: Autophagy
https://www.readbyqxmd.com/read/28315422/sfpq-psf-tfe3-renal-cell-carcinoma-rcc-a-clinicopathologic-study-emphasizing-extended-morphology-and-reviewing-the-differences-between-sfpq-tfe3-rcc-and-the-corresponding-mesenchymal-neoplasm-despite-an-identical-gene-fusion
#15
Xiao-Tong Wang, Qiu-Yuan Xia, Hao Ni, Sheng-Bing Ye, Rui Li, Xuan Wang, Shan-Shan Shi, Xiao-Jun Zhou, Qiu Rao
Xp11 translocation renal cell carcinoma (RCC) with SFPQ/PSF-TFE3 gene fusion is a rare epithelial tumor. Of note, the appearance of the gene fusion does not necessarily mean that it is renal cell carcinoma. The corresponding mesenchymal neoplasms, including Xp11 neoplasm with melanocytic differentiation, TFE3 rearrangement-associated perivascular epithelioid cell tumor (PEComa) and melanotic Xp11 translocation renal cancer, can also harbor the identical gene fusion. However, the differences between Xp11 translocation RCC and the corresponding mesenchymal neoplasm have only recently been described...
March 14, 2017: Human Pathology
https://www.readbyqxmd.com/read/28315332/nuclear-ampk-regulated-carm1-stabilization-impacts-autophagy-in-aged-heart
#16
Chen Li, Lu Yu, Han Xue, Zheng Yang, Yue Yin, Bo Zhang, Mai Chen, Heng Ma
Senescence-associated autophagy downregulation leads to cardiomyocyte dysfunction. Coactivator-associated arginine methyltransferase 1 (CARM1) participates in many cellular processes, including autophagy in mammals. However, the effect of CARM1 in aging-related cardiac autophagy decline remains undefined. Moreover, AMP-activated protein kinase (AMPK) is a key regulator in metabolism and autophagy, however, the role of nuclear AMPK in autophagy outcome in aged hearts still unclear. Hers we identify the correlation between nuclear AMPK and CARM1 in aging heart...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28301521/lysosomal-adaptation-how-cells-respond-to-lysosomotropic-compounds
#17
Shuyan Lu, Tae Sung, Nianwei Lin, Robert T Abraham, Bart A Jessen
Lysosomes are acidic organelles essential for degradation and cellular homoeostasis and recently lysosomes have been shown as signaling hub to respond to the intra and extracellular changes (e.g. amino acid availability). Compounds including pharmaceutical drugs that are basic and lipophilic will become sequestered inside lysosomes (lysosomotropic). How cells respond to the lysosomal stress associated with lysosomotropism is not well characterized. Our goal is to assess the lysosomal changes and identify the signaling pathways that involve in the lysosomal changes...
2017: PloS One
https://www.readbyqxmd.com/read/28292013/the-tumor-suppressor-p53-regulates-autophagosomal-and-lysosomal-biogenesis-in-lung-cancer-cells-by-targeting-transcription-factor-eb
#18
Zengli Zhang, Hongfeng Wang, Qifeng Ding, Yufei Xing, Delai Xu, Zhonghua Xu, Tong Zhou, Bin Qian, Chenghong Ji, Xue Pan, Anyuan Zhong, Zheng Ying, Caicun Zhou, Minhua Shi
The cellular protein degradation system, such as proteasomal or autophagy-lysosomal system plays an important role in the pathogenesis of a variety of human diseases including cancer. Transcription factor EB (TFEB) is a master transcriptional factor in the regulation of autophagy-lysosome pathway (ALP), and it has multiple biological functions including protein degradation, cell homeostasis and cell survival. In the present study we show that the tumor suppressor p53 can regulate TFEB nuclear translocation and activity in lung cancer cells...
March 10, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28288037/xp11-translocation-renal-cell-carcinomas-rccs-with-rbm10-tfe3-gene-fusion-demonstrating-melanotic-features-and-overlapping-morphology-with-t-6-11-rcc-interest-and-diagnostic-pitfall-in-detecting-a-paracentric-inversion-of-tfe3
#19
Qiu-Yuan Xia, Xiao-Tong Wang, Xue-Mei Zhan, Xiao Tan, Hao Chen, Yi Liu, Shan-Shan Shi, Xuan Wang, Xue Wei, Sheng-Bing Ye, Rui Li, Heng-Hui Ma, Zhen-Feng Lu, Xiao-Jun Zhou, Qiu Rao
Xp11 translocation renal cell carcinomas (RCC) are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathologic manifestations. Only 3 RBM10-TFE3 RCCs have been reported to date. Here, we added 4 cases of this rare type of tumors with clinicopathologic, immunohistochemical, molecular, and ultrastructural analyses. Most tumors had similar patterns with mixed architectures as follows: acinar, tubular and papillary patterns of epithelioid cells combined with sheets of small cells with "pseudorosette-like" architectures, mimicking the typical morphology of t(6;11) RCC...
May 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28283651/tfe3-regulates-whole-body-energy-metabolism-in-cooperation-with-tfeb
#20
Nunzia Pastore, Anna Vainshtein, Tiemo J Klisch, Andrea Armani, Tuong Huynh, Niculin J Herz, Elena V Polishchuk, Marco Sandri, Andrea Ballabio
TFE3 and TFEB are members of the MiT family of HLH-leucine zipper transcription factors. Recent studies demonstrated that they bind overlapping sets of promoters and are post-transcriptionally regulated through a similar mechanism. However, while Tcfeb knockout (KO) mice die during early embryonic development, no apparent phenotype was reported in Tfe3 KO mice. Thus raising the need to characterize the physiological role of TFE3 and elucidate its relationship with TFEB TFE3 deficiency resulted in altered mitochondrial morphology and function both in vitro and in vivo due to compromised mitochondrial dynamics...
March 10, 2017: EMBO Molecular Medicine
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