scholarly journals The Rab32/BLOC-3 dependent pathway mediates host- defence against different pathogens in human macrophages

2019 ◽  
Author(s):  
Massimiliano Baldassarre ◽  
Virtu Solano-Collado ◽  
Arda Balci ◽  
Rosa A. Colamarino ◽  
Ivy M Dambuza ◽  
...  
Keyword(s):  
Oxidative Burst ◽  
Mammalian Species ◽  
Host Defence ◽  
Intracellular Pathogens ◽  
Nucleotide Exchange ◽  
Human Macrophages ◽  
Guanine Nucleotide Exchange ◽  
Trafficking Pathway ◽  
Nucleotide Exchange Factor ◽  
Wide Range

ABSTRACTMacrophages provide a first line of defence against microorganisms, and while some mechanisms to kill pathogens such as the oxidative burst are well described, others are still undefined or unknown. Here we report that the Rab32 GTPase and its guanine nucleotide exchange factor BLOC-3 are central components of a trafficking pathway that controls both bacterial and fungal intracellular pathogens. This broad host-defence mechanism is active in both human and murine macrophages and is independent of well known antimicrobial mechanisms such as the NADPH-dependent oxidative burst, production of nitric oxide and antimicrobial peptides. To survive in human macrophages, Salmonella Typhi actively counteracts the Rab32/BLOC-3 pathway through its Salmonella pathogenicity island-1-encoded type III secretion system. These findings demonstrate that the Rab32/BLOC-3 pathway is a novel and universal host-defence pathway and protects mammalian species from a wide range of intracellular pathogens.

scholarly journals Induction of cell retraction by the combined actions of Abl–CrkII and Rho–ROCK1 signaling

2008 ◽  
Vol 183 (4) ◽  
pp. 711-723 ◽  
Author(s):  
XiaoDong Huang ◽  
Diana Wu ◽  
Hua Jin ◽  
Dwayne Stupack ◽  
Jean Y.J. Wang
Keyword(s):  
Nucleotide Exchange ◽  
Downstream Target ◽  
Abl Tyrosine Kinase ◽  
Guanine Nucleotide Exchange ◽  
Cell Matrix ◽  
Nucleotide Exchange Factor ◽  
Wide Range ◽  
Important Regulator ◽  
Guanosine Triphosphatase ◽  
Cell Retraction

Dynamic modulation of cell adhesion is integral to a wide range of biological processes. The small guanosine triphosphatase (GTPase) Rap1 is an important regulator of cell–cell and cell–matrix adhesions. We show here that induced expression of activated Abl tyrosine kinase reduces Rap1-GTP levels through phosphorylation of Tyr221 of CrkII, which disrupts interaction of CrkII with C3G, a guanine nucleotide exchange factor for Rap1. Abl-dependent down-regulation of Rap1-GTP causes cell rounding and detachment only when the Rho–ROCK1 pathway is also activated, for example, by lysophosphatidic acid (LPA). During ephrin-A1–induced retraction of PC3 prostate cancer cells, we show that endogenous Abl is activated and disrupts the CrkII–C3G complex to reduce Rap1-GTP. Interestingly, ephrin-A1–induced PC3 cell retraction also requires LPA, which stimulates Rho to a much higher level than that is activated by ephrin-A1. Our results establish Rap1 as another downstream target of the Abl–CrkII signaling module and show that Abl–CrkII collaborates with Rho–ROCK1 to stimulate cell retraction.

scholarly journals Amino acids stimulate the endosome-to-Golgi trafficking through Ragulator and small GTPase Arl5

2018 ◽  
Author(s):  
Meng Shi ◽  
Bing Chen ◽  
Boon Kim Boh ◽  
Yan Zhou ◽  
Divyanshu Mahajan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Small Gtpase ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Retrograde Trafficking ◽  
Guanine Nucleotide Exchange ◽  
Trafficking Pathway ◽  
Nucleotide Exchange Factor ◽  
Mtorc1 Signaling ◽  
Nutrient Signaling

AbstractThe endosome-to-Golgi or endocytic retrograde trafficking pathway is an important post-Golgi recycling route. We made a novel discovery that the retrograde trafficking of cargos is inhibited and stimulated by the absence and presence, respectively, of amino acids (AAs), especially glutamine. By testing components of the AA-stimulated mTORC1 signaling pathway, we demonstrated that SLC38A9, v-ATPase and Ragulator, but not Rag GTPases and mTORC1, are essential for the AA-stimulated trafficking. Arl5, an ARF-like family small GTPase, interacts with Ragulator in an AA-regulated manner and both Arl5 and its effector, the Golgi-associated retrograde protein complex (GARP), are required for the AA-stimulated trafficking. We have therefore identified a mechanistic connection between the nutrient signaling and the retrograde trafficking pathway, whereby SLC38A9 and v-ATPase sense AA-sufficiency and Ragulator functions as a guanine nucleotide exchange factor to activate Arl5, which, together with GARP, a tethering factor, probably facilitates the endosome-to-Golgi trafficking.

scholarly journals The Rab32/BLOC-3–dependent pathway mediates host defense against different pathogens in human macrophages

2021 ◽  
Vol 7 (3) ◽  
pp. eabb1795
Author(s):  
Massimiliano Baldassarre ◽  
Virtu Solano-Collado ◽  
Arda Balci ◽  
Rosa A. Colamarino ◽  
Ivy M. Dambuza ◽  
...  
Keyword(s):  
Host Defense ◽  
Oxidative Burst ◽  
Defense Mechanism ◽  
Mammalian Species ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reduced Form ◽  
Nucleotide Exchange ◽  
Human Macrophages ◽  
Guanosine Triphosphatase ◽  
Lysosome Related Organelles

Macrophages provide a first line of defense against microorganisms, and while some mechanisms to kill pathogens such as the oxidative burst are well described, others are still undefined or unknown. Here, we report that the Rab32 guanosine triphosphatase and its guanine nucleotide exchange factor BLOC-3 (biogenesis of lysosome-related organelles complex–3) are central components of a trafficking pathway that controls both bacterial and fungal intracellular pathogens. This host-defense mechanism is active in both human and murine macrophages and is independent of well-known antimicrobial mechanisms such as the NADPH (reduced form of nicotinamide adenine dinucleotide phosphate)–dependent oxidative burst, production of nitric oxide, and antimicrobial peptides. To survive in human macrophages, Salmonella Typhi actively counteracts the Rab32/BLOC-3 pathway through its Salmonella pathogenicity island-1–encoded type III secretion system. These findings demonstrate that the Rab32/BLOC-3 pathway is a novel and universal host-defense pathway and protects mammalian species from various pathogens.

scholarly journals Biochemical and NMR characterization of the interactions of Vav2–SH2 domain with lipids and the EphA2 juxtamembrane region on membrane

2020 ◽  
Vol 477 (19) ◽  
pp. 3791-3801
Author(s):  
Liang Ge ◽  
Bo Wu ◽  
Youjia Zhang ◽  
Jiarong Wang ◽  
Hongxin Zhao ◽  
...  
Keyword(s):  
Lipid Membrane ◽  
Lipid Binding ◽  
Sh2 Domain ◽  
Nucleotide Exchange ◽  
Surface Receptors ◽  
Guanine Nucleotide Exchange ◽  
Juxtamembrane Region ◽  
Nucleotide Exchange Factor ◽  
Nmr Characterization ◽  
Wide Range

Vav2 is a ubiquitous guanine nucleotide exchange factor (GEF) for Rho family GTPases that is involved in regulating a wide range of biological processes. It interacts with several tyrosine-phosphorylated cell surface receptors, including the Eph family receptors, through its SH2 domain. The interaction of Vav2 with EphA2 is crucial for EphA2-mediated tumor angiogenesis. Here we show that Vav2–SH2 domain is a lipid-binding module that can recognize PI(4,5)P2 and PI(3,4,5)P3 lipids weakly but specifically. The specific lipid-binding site in Vav2–SH2 domain was identified by NMR chemical shift perturbation experiments using the head groups of PI(4,5)P2 and PI(3,4,5)P3, both of which bind to Vav2–SH2 with millimolar binding affinities. In addition, the interaction between Vav2–SH2 and the phosphorylated juxtamembrane region (JM) of EphA2 (Y594 phosphorylated) was investigated using NMR techniques. Furthermore, by using a nickel–lipid containing peptide-based nanodiscs system, we studied the binding of Vav2–SH2 to the phosphorylated JM region of EphA2 on lipid membrane and uncovered a role of membrane environment in modulating this protein–protein recognition.

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