scholarly journals A novel Rab11-Rab3a cascade required for lysosome exocytosis

2021 ◽  
Author(s):  
Cristina Escrevente ◽  
Liliana Bento-Lopes ◽  
José S Ramalho ◽  
Duarte C Barral
Keyword(s):  
Plasma Membrane ◽  
Cell Periphery ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Membrane Repair ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Plasma Membrane Repair ◽  
Molecular Machinery

AbstractLysosomes are dynamic organelles, capable of undergoing exocytosis. This process is crucial for several cellular functions, namely plasma membrane repair. Nevertheless, the molecular machinery involved in this process is poorly understood.Here, we identify Rab11a and Rab11b as regulators of calcium-induced lysosome exocytosis. Interestingly, Rab11-positive vesicles transiently interact with lysosomes at the cell periphery, indicating that this interaction is required for the last steps of lysosome exocytosis. Additionally, we found that the silencing of the exocyst subunit Sec15, a Rab11 effector, impairs lysosome exocytosis independently of the exocyst complex, suggesting that Sec15 acts together with Rab11 in the regulation of lysosome exocytosis. Furthermore, we show that Rab11 binds the guanine nucleotide exchange factor for Rab3a (GRAB) and also Rab3a, which we described previously as a regulator of the positioning and exocytosis of lysosomes.Thus, our studies suggest that Rab11-positive vesicles transport GRAB to activate Rab3a on lysosomes, establishing a Rab11-Rab3 cascade that is essential for lysosome exocytosis.

scholarly journals Rab11 is required for lysosome exocytosis through the interaction with Rab3a, Sec15 and GRAB

2021 ◽  
Author(s):  
Cristina Escrevente ◽  
Liliana Bento-Lopes ◽  
José S. Ramalho ◽  
Duarte C. Barral
Keyword(s):  
Plasma Membrane ◽  
Cell Periphery ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Membrane Repair ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Plasma Membrane Repair ◽  
Molecular Machinery

Lysosomes are dynamic organelles, capable of undergoing exocytosis. This process is crucial for several cellular functions, namely plasma membrane repair. Nevertheless, the molecular machinery involved in this process is poorly understood. Here, we identify Rab11a and Rab11b as regulators of calcium-induced lysosome exocytosis. Interestingly, Rab11-positive vesicles transiently interact with lysosomes at the cell periphery, indicating that this interaction is required for the last steps of lysosome exocytosis. Additionally, we found that the silencing of the exocyst subunit Sec15, a Rab11 effector, impairs lysosome exocytosis, suggesting that Sec15 acts together with Rab11 in the regulation of lysosome exocytosis. Furthermore, we show that Rab11 binds the guanine nucleotide exchange factor for Rab3a (GRAB) and also Rab3a, which we described previously as a regulator of the positioning and exocytosis of lysosomes. Thus, our study identifies new players required for lysosome exocytosis and suggest the existence of a Rab11-Rab3a cascade involved in this process.

scholarly journals The RAP1 Guanine Nucleotide Exchange Factor Epac2 Couples Cyclic AMP and Ras Signals at the Plasma Membrane

2005 ◽  
Vol 281 (5) ◽  
pp. 2506-2514 ◽  
Author(s):  
Yu Li ◽  
Sirisha Asuri ◽  
John F. Rebhun ◽  
Ariel F. Castro ◽  
Nivanka C. Paranavitana ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cyclic Amp ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

scholarly journals Active Arf6 Recruits ARNO/Cytohesin GEFs to the PM by Binding Their PH Domains

2007 ◽  
Vol 18 (6) ◽  
pp. 2244-2253 ◽  
Author(s):  
Lee Ann Cohen ◽  
Akira Honda ◽  
Peter Varnai ◽  
Fraser D. Brown ◽  
Tamas Balla ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Family Member ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Ph Domain ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Biochemical Assays ◽  
Inositol Phospholipids ◽  
Sec7 Domain

ARNO is a soluble guanine nucleotide exchange factor (GEF) for the Arf family of GTPases. Although in biochemical assays ARNO prefers Arf1 over Arf6 as a substrate, its localization in cells at the plasma membrane (PM) suggests an interaction with Arf6. In this study, we found that ARNO activated Arf1 in HeLa and COS-7 cells resulting in the recruitment of Arf1 on to dynamic PM ruffles. By contrast, Arf6 was activated less by ARNO than EFA6, a canonical Arf6 GEF. Remarkably, Arf6 in its GTP-bound form recruited ARNO to the PM and the two proteins could be immunoprecipitated. ARNO binding to Arf6 was not mediated through the catalytic Sec7 domain, but via the pleckstrin homology (PH) domain. Active Arf6 also bound the PH domain of Grp1, another ARNO family member. This interaction was direct and required both inositol phospholipids and GTP. We propose a model of sequential Arf activation at the PM whereby Arf6-GTP recruits ARNO family GEFs for further activation of other Arf isoforms.

scholarly journals Identification of a Plasma Membrane-associated Guanine Nucleotide Exchange Factor for ARF6 in Chromaffin Cells

2000 ◽  
Vol 275 (21) ◽  
pp. 15637-15644 ◽  
Author(s):  
Anne-Sophie Caumont ◽  
Nicolas Vitale ◽  
Marc Gensse ◽  
Marie-Christine Galas ◽  
James E. Casanova ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Chromaffin Cells ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

scholarly journals A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair

2016 ◽  
Vol 213 (6) ◽  
pp. 631-640 ◽  
Author(s):  
Marisa Encarnação ◽  
Lília Espada ◽  
Cristina Escrevente ◽  
Denisa Mateus ◽  
José Ramalho ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Cell Periphery ◽  
Perinuclear Region ◽  
Nonmuscle Myosin ◽  
Membrane Repair ◽  
Rab Family ◽  
Plasma Membrane Repair ◽  
Molecular Machinery

Lysosome exocytosis plays a major role in resealing plasma membrane (PM) disruptions. This process involves two sequential steps. First, lysosomes are recruited to the periphery of the cell and then fuse with the damaged PM. However, the trafficking molecular machinery involved in lysosome exocytosis and PM repair (PMR) is poorly understood. We performed a systematic screen of the human Rab family to identify Rabs required for lysosome exocytosis and PMR. Rab3a, which partially localizes to peripheral lysosomes, was one of the most robust hits. Silencing of Rab3a or its effector, synaptotagmin-like protein 4a (Slp4-a), leads to the collapse of lysosomes to the perinuclear region and inhibition of PMR. Importantly, we have also identified a new Rab3 effector, nonmuscle myosin heavy chain IIA, as part of the complex formed by Rab3a and Slp4-a that is responsible for lysosome positioning at the cell periphery and lysosome exocytosis.

scholarly journals ARL3 and ARL13B GTPases participate in distinct steps of INPP5E targeting to the ciliary membrane

Biology Open ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Sayaka Fujisawa ◽  
Hantian Qiu ◽  
Shohei Nozaki ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factor ◽  
Membrane Localization ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Ciliary Membrane ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Direct Binding ◽  
Ciliary Localization

ABSTRACT INPP5E, a phosphoinositide 5-phosphatase, localizes on the ciliary membrane via its C-terminal prenyl moiety, and maintains the distinct ciliary phosphoinositide composition. The ARL3 GTPase contributes to the ciliary membrane localization of INPP5E by stimulating the release of PDE6D bound to prenylated INPP5E. Another GTPase, ARL13B, which is localized on the ciliary membrane, contributes to the ciliary membrane retention of INPP5E by directly binding to its ciliary targeting sequence. However, as ARL13B was shown to act as a guanine nucleotide exchange factor (GEF) for ARL3, it is also possible that ARL13B indirectly mediates the ciliary INPP5E localization via activating ARL3. We here show that INPP5E is delocalized from cilia in both ARL3-knockout (KO) and ARL13B-KO cells. However, some of the abnormal phenotypes were different between these KO cells, while others were found to be common, indicating the parallel roles of ARL3 and ARL13B, at least concerning some cellular functions. For several variants of ARL13B, their ability to interact with INPP5E, rather than their ability as an ARL3-GEF, was associated with whether they could rescue the ciliary localization of INPP5E in ARL13B-KO cells. These observations together indicate that ARL13B determines the ciliary localization of INPP5E, mainly by its direct binding to INPP5E.

scholarly journals Inositol phospholipids regulate the guanine-nucleotide-exchange factor Tiam1 by facilitating its binding to the plasma membrane and regulating GDP/GTP exchange on Rac1

2004 ◽  
Vol 382 (3) ◽  
pp. 857-865 ◽  
Author(s):  
Ian N. FLEMING ◽  
Ian H. BATTY ◽  
Alan R. PRESCOTT ◽  
Alex GRAY ◽  
Gursant S. KULAR ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Inositol Phosphates ◽  
Pleckstrin Homology Domain ◽  
Membrane Association ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Pleckstrin Homology ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

Binding of the Rac1-specific guanine-nucleotide-exchange factor, Tiam1, to the plasma membrane requires the N-terminal pleckstrin homology domain. In the present study, we show that membrane-association is mediated by binding of PtdIns(4,5)P2 to the pleckstrin homology domain. Moreover, in 1321N1 astrocytoma cells, translocation of Tiam1 to the cytosol, following receptor-mediated stimulation of PtdIns(4,5)P2 breakdown, correlates with decreased Rac1-GTP levels, indicating that membrane-association is required for GDP/GTP exchange on Rac1. In addition, we show that platelet-derived growth factor activates Rac1 in vivo by increasing PtdIns(3,4,5)P3 concentrations, rather than the closely related lipid, PtdIns(3,4)P2. Finally, the data demonstrate that PtdIns(4,5)P2 and PtdIns(3,4,5)P3 bind to the same pleckstrin homology domain in Tiam1 and that soluble inositol phosphates appear to compete with lipids for this binding. Together, these novel observations provide strong evidence that distinct phosphoinositides regulate different functions of this enzyme, indicating that local concentrations of signalling lipids and the levels of cytosolic inositol phosphates will play crucial roles in determining its activity in vivo.

Multiple Phosphorylation Sites and Quaternary Organization of Guanine-Nucleotide Exchange Complex of Elongation Factor-1 (EF-1βγδ/ValRS) Control the Various Functions of EF-1α

1998 ◽  
Vol 18 (3) ◽  
pp. 119-127 ◽  
Author(s):  
Odile Minella ◽  
Odile Mulner-Lorillon ◽  
Guillaume Bec ◽  
Patrick Cormier ◽  
Robert Bellé
Keyword(s):  
Structural Model ◽  
Elongation Factor ◽  
Trna Synthetase ◽  
Macromolecular Complex ◽  
Phosphorylation Sites ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

The eukaryotic guanine-nucleotide exchange factor commonly called elongation factor-1βγδ (EF-1βγδ), comprises four different subunits including valyl-tRNA synthetase (EF-1βγδ/ValRS). The factor is multiply-phosphorylated by three different protein kinases, protein kinase C, casein kinase II and cyclin dependent kinase 1 (CDK1). EF-1βγδ/ValRS is organized as a macromolecular complex for which we propose a new structural model. Evidence that EF-1βγδ/ValRS is a sophisticated supramolecular complex containing many phosphorylation sites, makes it a potential regulator of any of the functions of its partner EF-1α, not only involved in protein synthesis elongation, but also in many other cellular functions.

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