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https://www.readbyqxmd.com/read/28336235/tyrosine-phosphorylation-of-rab7-by-src-kinase
#1
Xiaosi Lin, Jiaming Zhang, Lingqiu Chen, Yongjun Chen, Xiaohui Xu, Wanjin Hong, Tuanlao Wang
The small molecular weight GTPase Rab7 is a key regulator for late endosomal/lysosomal membrane trafficking, it was known that Rab7 is phosphorylated, but the corresponding kinase and the functional regulation of Rab7 phosphorylation remain unclear. We provide evidence here that Rab7 is a substrate of Src kinase, and is tyrosine-phosphorylated by Src, withY183 residue of Rab7 being the optimal phosphorylation site for Src. Further investigations demonstrated that the tyrosine phosphorylation of Rab7 depends on the guanine nucleotide binding activity of Rab7 and the activity of Src kinase...
March 20, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28330474/hypercholesterolemia-downregulates-autophagy-in-the-rat-heart
#2
Zoltán Giricz, Gábor Koncsos, Tomáš Rajtík, Zoltán V Varga, Tamás Baranyai, Csaba Csonka, Adrián Szobi, Adriana Adameová, Roberta A Gottlieb, Péter Ferdinandy
BACKGROUND: We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart...
March 23, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/28325809/the-rab7-effector-plekhm1-binds-arl8b-to-promote-cargo-traffic-to-lysosomes
#3
Rituraj Marwaha, Subhash B Arya, Divya Jagga, Harmeet Kaur, Amit Tuli, Mahak Sharma
Endocytic, autophagic, and phagocytic vesicles move on microtubule tracks to fuse with lysosomes. Small GTPases, such as Rab7 and Arl8b, recruit their downstream effectors to mediate this transport and fusion. However, the potential cross talk between these two GTPases is unclear. Here, we show that the Rab7 effector PLEKHM1 simultaneously binds Rab7 and Arl8b, bringing about clustering and fusion of late endosomes and lysosomes. We show that the N-terminal RUN domain of PLEKHM1 is necessary and sufficient for interaction with Arl8b and its subsequent localization to lysosomes...
March 21, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28317806/mycobacterium-lepraemurium-uses-tlr-6-and-mr-but-not-lipid-rafts-or-dc-sign-to-gain-access-into-mouse-macrophages
#4
Mayra Silva-Miranda, Patricia Arce-Paredes, Oscar Rojas-Espinosa
OBJECTIVE/BACKGROUND: Mycobacterium lepraemurium (MLM), the etiologic agent of murine leprosy, is an intracellular parasite of macrophages; the mechanism used by this bacterium to enter macrophages is not known. The fate of the MLM phagosome inside macrophages is also unknown. This study was conducted to investigate how MLM enters macrophages and to define the maturation process of MLM phagosome inside macrophages. MATERIALS AND METHODS: Peritoneal macrophages were incubated in the presence of mannan-bovine serum albumin (BSA), and antibodies to known macrophage receptors, including, anti-FcγRIII/RII (anti-CD16/32), anti-CD35 (anti-CR1), anti-TLR2, anti-TLR4, anti-TLR6, anti-CD14, and anti-dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)...
January 2017: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28291748/the-crystal-structure-of-mouse-lc3b-in-complex-with-the-fyco1-lir-reveals-the-importance-of-the-flanking-region-of-the-lir-motif
#5
Shunya Sakurai, Taisuke Tomita, Toshiyuki Shimizu, Umeharu Ohto
FYVE and coiled-coil domain-containing protein 1 (FYCO1), a multidomain autophagy adaptor protein, mediates microtubule plus-end-directed autophagosome transport by interacting with kinesin motor proteins and with the autophagosomal membrane components microtubule-associated protein 1 light chain 3 (LC3), Rab7 and phosphatidylinositol 3-phosphate (PI3P). To establish the structural basis for the recognition of FYCO1 by LC3, the crystal structure of mouse LC3B in complex with the FYCO1 LC3-interacting region (LIR) motif peptide was determined...
March 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/28275133/ppar-%C3%AE-activation-mediates-innate-host-defense-through-induction-of-tfeb-and-lipid-catabolism
#6
Yi Sak Kim, Hye-Mi Lee, Jin Kyung Kim, Chul-Su Yang, Tae Sung Kim, Mingyu Jung, Hyo Sun Jin, Sup Kim, Jichan Jang, Goo Taeg Oh, Jin-Man Kim, Eun-Kyeong Jo
The role of peroxisome proliferator-activated receptor α (PPAR-α) in innate host defense is largely unknown. In this study, we show that PPAR-α is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-α deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-α agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against Mycobacterium tuberculosis or M...
March 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28264927/missing-in-metastasis-protein-downregulates-cxcr4-by-promoting-ubiquitination-and-interaction-with-small-rab-gtpases
#7
Lushen Li, Shaneen S Baxter, Ning Gu, Min Ji, Xi Zhan
Surface expression of chemokine receptor CXCR4 is downregulated by MIM, a member of the inverse BAR (I-BAR) domain protein family that recognizes and generates membranes with negative curvatures. Yet, the mechanism for the regulation is unknown. Here, we showed that MIM formed a complex with CXCR4 via binding to E3 ubiquitin ligase AIP4 in response to SDF-1. Overexpression of MIM promoted CXCR4 ubiquitination, inhibited cellular response to SDF-1, caused accumulation and aggregation of MVBs in the cytoplasm, and promoted CXCR4 sorting into MVBs in a manner depending on binding to AIP4...
March 6, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28225130/systematic-investigation-on-the-intracellular-trafficking-network-of-polymeric-nanoparticles
#8
Jinxie Zhang, Danfeng Chang, Yao Yang, Xudong Zhang, Wei Tao, Lijuan Jiang, Xin Liang, Hsiangi Tsai, Laiqiang Huang, Lin Mei
Polymeric nanoparticles such as PLGA-based nanoparticles are emerging as promising carriers for controlled drug delivery. However, little is known about the intracellular trafficking network of polymeric nanoparticles. Here, more than 30 Rab proteins were used as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy to investigate in detail the intracellular trafficking pathways of PLGA nanoparticles. We observed that coumarin-6-loaded PLGA nanoparticles were internalized by the cells mainly through caveolin and clathrin-dependent endocytosis and Rab34-mediated macropinocytosis...
February 22, 2017: Nanoscale
https://www.readbyqxmd.com/read/28222213/rab7a-regulates-tau-secretion
#9
Lilia Rodriguez, Nguyen-Vi Mohamed, Alexandre Desjardins, Roger Lippé, Edward Fon, Nicole Leclerc
The axonal microtubule-associated protein TAU, involved in Alzheimer's disease (AD), can be found in the extracellular space where it could be taken up by neurons, an event that is believed to contribute to the propagation of tau pathology in the brain. Since the small GTPase Rab7A is involved in the trafficking of endosomes, autophagosomes and lysosomes, and RAB7A gene expression and protein levels are upregulated in AD patients, we tested the hypothesis that Rab7A was involved in Tau secretion. We previously reported that both primary cortical neurons and HeLa cells overexpressing human TAU can release Tau...
February 21, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28213273/2-methoxyestradiol-protects-against-ischemia-reperfusion-injury-in-alcoholic-fatty-liver-by-enhancing-sirtuin-1-mediated-autophagy
#10
Hong-Ik Cho, Min-Jong Seo, Sun-Mee Lee
Alcoholic fatty liver (AFL) is susceptible to ischemia/reperfusion (I/R) injury, responding with inflammation and extensive hepatocellular damage. Autophagy maintains cellular homeostasis and regulates inflammation and lipid metabolism. 2-Methoxyestradiol (2-ME2), an endogenous metabolite of estradiol, exhibits antioxidant and anti-inflammatory properties. This study examined the cytoprotective mechanisms of 2-ME2 on hepatic I/R in AFL, focusing on autophagy signaling. C57BL/6 mice were fed an ethanol diet (ED) to induce AFL, or a control diet (CD) for 6weeks, and then subjected to 60min of ischemia and 5h of reperfusion...
February 16, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28186670/rab7-may-be-a-novel-therapeutic-target-for-neurologic-diseases-as-a-key-regulator-in-autophagy
#11
REVIEW
Haixia Wen, Lixuan Zhan, Siyuan Chen, Long Long, En Xu
Macroautophagy is an evolutionally conserved membrane trafficking pathway that delivers intracellular materials to lysosomes for degradation and recycling. Rab7, as a member of the Rab GTPase superfamily, has a unique role in the regulation of macroautophagy, especially in modulating autophagy flux. The functional states of Rab7 generally switch between GTP-bound and GDP-bound states under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated GTP-Rab7 is capable of regulating autophagosome formation, autophagosome transportation along microtubules, endosome and autophagosome maturation, as well as lysosome biogenesis via interacting with its effector molecules...
February 10, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28185347/salmonella-effector-sopd2-interferes-with-rab34-function
#12
Wei Xuan Teo, Zhe Yang, Markus Charles Kerr, Lin Luo, Zhong Guo, Kirill Alexandrov, Jenny Lea Stow, Rohan David Teasdale
Many intracellular pathogens have evolved highly specialized mechanisms to isolate themselves from the host cell's innate immune response while still obtaining the necessary nutrients to survive. Salmonella utilizes type 3 secretion systems (T3SSs) to deliver bacterial proteins called effectors, across the encompassing Salmonella Containing vacuole (SCV) membrane, to subvert the host's membrane trafficking pathways and alter other cellular processes. The Salmonella Pathogenicity Island (SPI)-2 effector SopD2 has recently been demonstrated to modulate multiple members of the Rab GTPase family such as Rab7, Rab8, Rab10, and Rab32 (D'Costa et al...
February 9, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28182007/prenatal-alcohol-exposure-impairs-autophagy-in-neonatal-brain-cortical-microvessels
#13
Virginie Girault, Vianney Gilard, Florent Marguet, Céline Lesueur, Michelle Hauchecorne, Yasmina Ramdani, Annie Laquerrière, Stéphane Marret, Sylvie Jégou, Bruno Jose Gonzalez, Carole Brasse-Lagnel, Soumeya Bekri
Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28180992/comprehensive-functional-analysis-of-rab-gtpases-in-drosophila-nephrocytes
#14
Yulong Fu, Jun-Yi Zhu, Fujian Zhang, Adam Richman, Zhanzheng Zhao, Zhe Han
The Drosophila nephrocyte is a critical component of the fly renal system and bears structural and functional homology to podocytes and proximal tubule cells of the mammalian kidney. Investigations of nephrocyte cell biological processes are fundamental to understanding the insect renal system. Nephrocytes are highly active in endocytosis and vesicle trafficking. Rab GTPases regulate endocytosis and trafficking but specific functions of nephrocyte Rabs remain undefined. We analyzed Rab GTPase expression and function in Drosophila nephrocytes and found that 11 out of 27 Drosophila Rabs were required for normal activity...
February 8, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28165391/charcot-marie-tooth-2b-peripheral-sensory-neuropathy-how-rab7-mutations-impact-ngf-signaling
#15
REVIEW
Harry Liu, Chengbiao Wu
Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s) enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy...
February 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28147319/mevastatin-blockade-of-autolysosome-maturation-stimulates-lbh589-induced-cell-death-in-triple-negative-breast-cancer-cells
#16
Zhaohu Lin, Zhuqing Zhang, Xiaoxiao Jiang, Xinhui Kou, Yong Bao, Huijuan Liu, Fanghui Sun, Shuang Ling, Ning Qin, Lan Jiang, Yonghua Yang
Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, and combining a HDACi with other agents is an attractive therapeutic strategy in solid tumors. We report here that mevastatin increases HDACi LBH589-induced cell death in triple-negative breast cancer (TNBC) cells. Combination treatment inhibited autophagic flux by preventing Vps34/Beclin 1 complex formation and downregulating prenylated Rab7, an active form of the small GTPase necessary for autophagosome-lysosome fusion. This means that co-treatment with mevastatin and LBH589 activated LKB1/AMPK signaling and subsequently inhibited mTOR...
January 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28145495/autophagic-flux-a-possible-mechanism-for-delayed-gentamicin-induced-ototoxicity
#17
Yeon Ju Kim, Chunjie Tian, Jangho Kim, Beomyong Shin, Oak-Sung Choo, You-Sun Kim, Yun-Hoon Choung
Aminoglycoside antibiotics including gentamicin (GM) induce delayed ototoxic effects such as hearing loss after long-term use, unlike the early-onset ototoxicity caused by cisplatin. The purpose of the study was to identify the mechanism of the delayed GM-induced ototoxicity by exploring the role of autophagy in vitro and in vivo. Treating HEI-OC1 auditory cells with GM led to a time-dependent increase of the autophagosome marker LC3-II, which was accompanied by cell death. In contrast, cisplatin and penicillin caused a rapid increase and had no effect on LC3-II levels, respectively...
February 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28129640/nuclear-transport-of-cancer-extracellular-vesicle-derived-biomaterials-through-nuclear-envelope-invagination-associated-late-endosomes
#18
Germana Rappa, Mark F Santos, Toni M Green, Jana Karbanová, Justin Hassler, Yongsheng Bai, Sanford H Barsky, Denis Corbeil, Aurelio Lorico
Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication, but how the biomaterials they carry reach the target site in recipient cells is an open question. We report that subdomains of Rab7+ late endosomes and nuclear envelope invaginations come together to create a sub-nuclear compartment, where biomaterials associated with CD9+ EVs are delivered. EV-derived biomaterials were also found in the nuclei of host cells. The inhibition of nuclear import and export pathways abrogated the nuclear localization of EV-derived biomaterials or led to their accumulation therein, respectively, suggesting that their translocation is dependent on nuclear pores...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28100639/munc13-4-functions-as-a-ca2-sensor-for-homotypic-secretory-granule-fusion-to-generate-endosomal-exocytic-vacuoles
#19
Sang Su Woo, Declan J James, Thomas F J Martin
Munc13-4 is a Ca(2+)-dependent SNARE- and phospholipid-binding protein that localizes to and primes secretory granules (SGs) for Ca(2+)-evoked secretion in various secretory cells. Studies in mast cell-like RBL-2H3 cells provides direct evidence that Munc13-4 with its two Ca(2+)-binding C2 domains functions as a Ca(2+) sensor for SG exocytosis. Unexpectedly, Ca(2+) stimulation also generated large (>2.4 μm diameter) Munc13-4(+)/Rab7(+)/Rab11(+) endosomal vacuoles. Vacuole generation involved the homotypic fusion of Munc13-4(+)/Rab7(+) SGs followed by a merge with Rab11(+) endosomes, and depended on Ca(2+) binding to Munc13-4...
January 18, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28100638/retromer-driven-membrane-tubulation-separates-endosomal-recycling-from-rab7-ypt7-dependent-fusion
#20
Latha Kallur Purushothaman, Henning Arlt, Anne Kuhlee, Stefan Raunser, Christian Ungermann
Endosomes are the major protein sorting hubs of the endocytic pathway. They sort proteins destined for degradation into internal vesicles, while in parallel recycling receptors via tubular carriers back to the Golgi. Tubule formation depends on the Rab7/Ypt7-interacting retromer complex, consisting of the sorting nexin dimer (SNX-BAR) and the trimeric cargo selection complex (CSC). Fusion of mature endosomes with the lysosome-like vacuole also requires Rab7/Ypt7. Here, we now solved a major problem in understanding this dual function of endosomal Rab7/Ypt7 using a fully reconstituted system, including purified, full-length yeast SNX-BAR and CSC, whose overall structure we present...
January 18, 2017: Molecular Biology of the Cell
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