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Toshifumi Fujiwara, Shiqiao Ye, Thiago Castro-Gomes, Caylin G Winchell, Norma W Andrews, Daniel E Voth, Kottayil I Varughese, Samuel G Mackintosh, Yunfeng Feng, Nathan Pavlos, Takashi Nakamura, Stavros C Manolagas, Haibo Zhao
Mutations of the Plekhm1 gene in humans and rats cause osteopetrosis, an inherited bone disease characterized by diminished bone resorption by osteoclasts. PLEKHM1 binds to RAB7 and is critical for lysosome trafficking. However, the molecular mechanisms by which PLEKHM1 regulates lysosomal pathways remain unknown. Here, we generated germline and conditional Plekhm1-deficient mice. These mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Furthermore, loss of PLEKHM1 abrogated the peripheral distribution of lysosomes and bone resorption in osteoclasts...
October 20, 2016: JCI Insight
Binod Kumar, Dipanjan Dutta, Jawed Iqbal, Mairaj Ahmed Ansari, Arunava Roy, Leela Chikoti, Gina Pisano, Mohanan Valiya Veettil, Bala Chandran
Kaposi's sarcoma-associated herpesvirus (KSHV) binding to the endothelial cell surface heparan sulfate is followed by sequential interactions with α3β1, αVβ3 and αVβ5 integrins and Ephrin A2 receptor tyrosine kinase (EphA2R). These interactions activate host cell pre-existing FAK, Src, PI3-K and RhoGTPase signaling cascades, c-Cbl mediated ubiquitination of receptors, recruitment of CIB1, p130Cas and Crk adaptor molecules, and membrane bleb formation leading to lipid raft dependent macropinocytosis of KSHV into human microvascular dermal endothelial (HMVEC-d) cells...
October 2016: PLoS Pathogens
Adam P Rofe, Luther J Davis, Jean L Whittingham, Elizabeth C Latimer-Bowman, Anthony J Wilkinson, Paul R Pryor
Rhodococcus equi (R. equi) is an important pulmonary pathogen in foals that often leads to the death of the horse. The bacterium harbors a virulence plasmid that encodes numerous virulence-associated proteins (Vaps) including VapA that is essential for intracellular survival inside macrophages. However, little is known about the precise function of VapA. Here, we demonstrate that VapA causes perturbation to late endocytic organelles with swollen endolysosome organelles having reduced Cathepsin B activity and an accumulation of LBPA, LC3 and Rab7...
October 19, 2016: MicrobiologyOpen
Tonika Lam, Dennis V Kulp, Rui Wang, Zheng Lou, Julia Taylor, Carlos E Rivera, Hui Yan, Qi Zhang, Zhonghua Wang, Hong Zan, Dmitri N Ivanov, Guangming Zhong, Paolo Casali, Zhenming Xu
IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the class-switched IgG autoantibody response in MRL/Fas(lpr/lpr) and C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Ras-related in brain 7 (Rab7), an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of lifespan. These were associated with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells...
October 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Yuantai Wu, Mehmet Takar, Andrea A Cuentas-Condori, Todd R Graham
NEO1 is an essential gene in budding yeast and belongs to a highly conserved subfamily of P-type ATPase genes that encode phospholipid flippases. Inactivation of temperature sensitive neo1(ts) alleles produces pleiomorphic defects in the secretory and endocytic pathways, including fragmented vacuoles. A screen for multicopy suppressors of neo1-2(ts) growth defects yielded YPT7, which encodes a Rab7 homolog involved in SNARE-dependent vacuolar fusion. YPT7 suppressed the vacuole fragmentation phenotype of neo1-2, but did not suppress Golgi-associated protein trafficking defects...
July 2016: Cellular Logistics
Jinxie Zhang, Xudong Zhang, Gan Liu, Danfeng Chang, Xin Liang, Xianbing Zhu, Wei Tao, Lin Mei
The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis...
2016: Theranostics
Romy E Verbeek, Peter D Siersema, Frank P Vleggaar, Fiebo J Ten Kate, George Posthuma, Rhonda F Souza, Judith de Haan, Jantine W P M van Baal
BACKGROUND AND AIMS: Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett's esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett's esophagus epithelium cell line...
September 2016: Journal of Gastrointestinal and Liver Diseases: JGLD
Veronica Astro, Diletta Tonoli, Sara Chiaretti, Sabrina Badanai, Kristyna Sala, Marino Zerial, Ivan de Curtis
Liprin-α1 and ERC1 are interacting scaffold proteins regulating the motility of normal and tumor cells. They act as part of plasma membrane-associated platforms at the edge of motile cells to promote protrusion by largely unknown mechanisms. Here we identify an amino-terminal region of the liprin-α1 protein (liprin-N) that is sufficient and necessary for the interaction with other liprin-α1 molecules. Similar to liprin-α1 or ERC1 silencing, expression of the liprin-N negatively affects tumor cell motility and extracellular matrix invasion, acting as a dominant negative by interacting with endogenous liprin-α1 and causing the displacement of the endogenous ERC1 protein from the cell edge...
2016: Scientific Reports
Sadek Ismail, Marie-Julie Gherardi, Alexander Froese, Madjid Zanoun, Véronique Gigoux, Pascal Clerc, Frederique Gaits-Iacovoni, Jan Steyaert, Viacheslav O Nikolaev, Daniel Fourmy
Until very recently, G-protein dependent signal of GPCRs was thought to originate exclusively from the plasma membrane and internalized GPCRs were considered silent. Here, we demonstrated that, once internalized and located in the membrane of early endosomes, glucose-dependent Insulinotropic receptor (GIPR) continues to trigger production of cAMP and PKA activation. Direct evidence is based on identification of the active form of Gαs in early endosomes containing GIPR using a genetically encoded GFP tagged nanobody, and on detection of a distinct FRET signal accounting for cAMP production at the surface of endosomes containing GIP, compared to endosomes without GIP...
September 15, 2016: Biochemical Pharmacology
Dong Hu, Wan Wang, Runpeng Zhao, Xuewei Xu, Yingru Xing, Shengfa Ni, Congjing Xu, Baoxian Tie, Rongbo Zhang, Jing Wu
Objective To study the role of Rab7 in the blockage of autophagosome-lysosome fusion induced by secretory acid phosphatase (SapM), a virulence factor of mycobacterium tuberculosis. Methods The Raw264.7 cells were transfected with siRab7, and the P62 was detected using Western blotting. After transfected with mCherry-SapM, the co-localization of SapM and Rab7 in Raw264.7 cells was detected by immunofluorescence cytochemistry and the interaction of SapM with Rab7 was determined by co-immunoprecipitation. SapM mutants including SapM(δ ARCA), SapM(δ FRED) and SapM(δ CT) were used to transfect Raw264...
September 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
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
Xiaolong Gu, Dandan Han, Wei Chen, Limei Zhang, Qianyun Lin, Jian Gao, Séamus Fanning, Bo Han
Fluorine may result in damage to teeth, bones and other body tissues, and is a serious public health problem. SIRT1 deacetylates FOXOs, which brings about apoptosis and autophagy promotion or suppression. Fluorine may induce cell apoptosis, however, the role of autophagy in apoptosis induced by fluorine is still poorly understood, and the interaction between SIRT1 and FOXOs should be further illustrated. Therefore, this study investigated the mechanisms underlying the NaF- induced apoptosis and autophagy in osteoblast-like MC3T3-E1 cells in vitro through activating or inhibiting SIRT1...
August 24, 2016: Oncotarget
Krisztina Hegedűs, Szabolcs Takáts, Attila Boda, András Jipa, Péter Nagy, Kata Varga, Attila L Kovács, Gábor Juhász
The small GTPase Rab5 promotes recruitment of the Ccz1-Mon1 guanosine exchange complex to endosomes to activate Rab7, which facilitates endosome maturation and fusion with lysosomes. How these factors function during autophagy is incompletely understood. Here we show that autophagosomes accumulate due to impaired fusion with lysosomes upon loss of the Ccz1-Mon1-Rab7 module in starved Drosophila fat cells. In contrast, autophagosomes generated in Rab5-null mutant cells normally fuse with lysosomes during the starvation response...
October 15, 2016: Molecular Biology of the Cell
Lee Dolat, Elias T Spiliotis
Macropinocytosis, the internalization of extracellular fluid and material by plasma membrane ruffles, is critical for antigen presentation, cell metabolism, and signaling. Macropinosomes mature through homotypic and heterotypic fusion with endosomes and ultimately merge with lysosomes. The molecular underpinnings of this clathrin-independent endocytic pathway are largely unknown. Here, we show that the filamentous septin GTPases associate preferentially with maturing macropinosomes in a phosphatidylinositol 3,5-bisphosphate-dependent manner and localize to their contact/fusion sites with macropinosomes/endosomes...
August 29, 2016: Journal of Cell Biology
Celina Amaya, Rodrigo D Militello, Sebastián D Calligaris, María I Colombo
Endocytosis is a multistep process engaged in extracellular molecules internalization. Several proteins including the Rab GTPases family coordinate the endocytic pathway. The small GTPase Rab7 is present in late endosome (LE) compartments being a marker of endosome maturation. The Rab interacting lysosomal protein (RILP) is a downstream effector of Rab7 that recruits the functional dynein/dynactin motor complex to late compartments. In the present study, we have found Rab24 as a component of the endosome-lysosome degradative pathway...
August 23, 2016: Traffic
Flora Guerra, Cecilia Bucci
Rab7 is a small GTPase that belongs to the Rab family and controls transport to late endocytic compartments such as late endosomes and lysosomes. The mechanism of action of Rab7 in the late endocytic pathway has been extensively studied. Rab7 is fundamental for lysosomal biogenesis, positioning and functions, and for trafficking and degradation of several signaling receptors, thus also having implications on signal transduction. Several Rab7 interacting proteins have being identified leading to the discovery of a number of different important functions, beside its established role in endocytosis...
August 18, 2016: Cells
Sergi Guixé-Muntet, Fernanda Cristina de Mesquita, Sergi Vila, Virginia Hernández-Gea, Carmen Peralta, Juan Carlos García-Pagán, Jaime Bosch, Jordi Gracia-Sancho
BACKGROUND & AIMS: The transcription factor Krüppel-like factor 2 (KLF2), inducible by simvastatin, confers endothelial vasoprotection. Considering recent data suggesting activation of autophagy by statins, we aimed to: 1) characterize the relationship between autophagy and KLF2 in the endothelium, 2) assess this relationship in acute liver injury (cold ischemia/reperfusion) and 3) study the effects of modulating KLF2-autophagy in vitro and in vivo. METHODS: Autophagic flux, the vasoprotective KLF2 pathway, cell viability and microvascular function were assessed in endothelial cells and in various pre-clinical models of acute liver injury (cold storage and warm reperfusion)...
August 18, 2016: Journal of Hepatology
Alina P Ryumina, Ekaterina O Serebrovskaya, Dmitry B Staroverov, Olga A Zlobovskaya, Alexander S Shcheglov, Sergey A Lukyanov, Konstantin A Lukyanov
Genetically encoded photosensitizers represent a promising optogenetic tool for the induction of light-controlled oxidative stress strictly localized to a selected intracellular compartment. Here we tested the phototoxic effects of the flavin-containing phototoxic protein miniSOG targeted to the cytoplasmic surfaces of late endosomes and lysosomes by fusion with Rab7. In HeLa Kyoto cells stably expressing miniSOG-Rab7, we demonstrated a high level of cell death upon blue-light illumination. Pepstatin A completely abolished phototoxicity of miniSOG-Rab7, showing a key role for cathepsin D in this model...
2016: BioTechniques
Jeong-Min Hong, Seok-Joo Kim, Sun-Mee Lee
Ischemia and reperfusion (I/R) is a complex phenomenon involving massive inflammation and cell death. Necroptosis refers to a newly described cell death as "programmed necrosis" that is controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, which is involved in the pathogenesis of several inflammatory diseases. Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli and involves crosstalk between different modes of cell death and inflammation. In this study, we investigated pattern changes in necroptosis and its role in autophagy signaling during hepatic I/R...
October 1, 2016: Toxicology and Applied Pharmacology
Gizele D Garcia, Eidy de O Santos, Gabriele V Sousa, Russolina B Zingali, Cristiane C Thompson, Fabiano L Thompson
Infectious diseases such as white plague syndrome (WPS) and black band disease (BBD) have caused massive coral loss worldwide. We performed a metaproteomic study on the Abrolhos coral Mussismilia braziliensis to define the types of proteins expressed in healthy corals compared to WPS- and BBD-affected corals. A total of 6363 MS/MS spectra were identified as 361 different proteins. Healthy corals had a set of proteins that may be considered markers of holobiont homoeostasis, including tubulin, histone, Rab family, ribosomal, peridinin-chlorophyll a-binding protein, F0F1-type ATP synthase, alpha-iG protein, calmodulin and ADP-ribosylation factor...
September 2016: Molecular Ecology
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