The Arf-like GTPase Arl8 Mediates Delivery of Endocytosed Macromolecules to Lysosomes in<i>Caenorhabditis elegans</i>

Nakae, Isei; Fujino, Tomoko; Kobayashi, Tetsuo; Sasaki, A; Kikko, Yorifumi; Fukuyama, Masamitsu; Gengyo-Ando, Keiko; Mitani, Shohei; Kontani, Kenji; Katada, Toshiaki

doi:10.1091/mbc.e09-12-1010

Cited by 77 publications

(68 citation statements)

References 55 publications

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“…Recent studies also suggested that Arl8b plays a role in lysosomal tubulation in macrophages and in Salmonellainfected cells, a process that requires the recruitment of kinesin motors (24,25). Separately, we found that Arl8b directs certain cargo into lysosomes in mammals by recruiting the VPS41 subunit of the tethering HOPS complex that mediates the fusion of late endosomes to lysosomes, whereas others defined a similar role for Arl8b in Caenorhabditis elegans (21,26,27).…”

supporting

confidence: 60%

MHC Class II Presentation Is Controlled by the Lysosomal Small GTPase, Arl8b

Michelet

Garg

Wolf

et al. 2015

The Journal of Immunology

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Dendritic cells (DCs) are specialized APCs with the ability to prime naive T cells. DCs first sample Ags from the environment and then orchestrate their processing and loading onto MHC class II (MHC II) Ag-presenting molecules in lysosomes. Once MHC II molecules have bound a peptide, the MHC II–peptide complex is delivered to the cell surface for presentation to CD4+ T cells. Regulation of Ag uptake via macropinocytosis and phagocytosis has been extensively studied, as well as trafficking in early endocytic vesicles notably regulated by the small GTPase Rab5 and its effectors. However, little is known about the regulators of Ag delivery from early endosomes to lysosomal compartments where the proper pH, proteases, MHC II, invariant chain, and HLA-DM reside, awaiting exogenous Ags for loading. In this article, we report the crucial role of the small GTPase ADP-ribosylation factor-like 8b (Arl8b) in MHC II presentation in DCs. We show for the first time, to our knowledge, that Arl8b localizes to MHC II compartments in DCs and regulates formation of MHC II–peptide complexes. Arl8b-silenced DCs display a defect in MHC II–Ag complex formation and its delivery to the cell surface during infection resulting in a defect in T cell recognition. Our results highlight the role of Arl8b as a trafficking regulator of the late stage of complex formation and MHC II presentation in DCs.

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supporting

confidence: 60%

MHC Class II Presentation Is Controlled by the Lysosomal Small GTPase, Arl8b

Michelet

Garg

Wolf

et al. 2015

The Journal of Immunology

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“…Loss of Arl8 gene in C. elegans increased the number of late endosomal compartments and impaired the degradation of endocytosed macromolecules due to abrogated fusion of late endosomes with lysosomes. 34 These findings were further reinforced in mammalian cells, wherein Arl8b depletion impaired the delivery of both fluid-phase (dextran and LDL) and membrane-bound (CD1d and MHC class II) cargo to the lysosomes. 23,45 As a result, Arl8b silencing impeded the display of antigen presentation complexes on the surface of dendritic cells and macrophages, and thereby impaired the activation of immune responses against these antigens.…”

Section: Arl8b Regulates Lysosomal Motility Through Interaction With mentioning

confidence: 87%

“…20,30,34 Recent studies in lysosomal trafficking field have revealed key functions of Arl8 ranging from microtubule-dependent motility to cargo degradation to the pathogenesis of intracellular microorganisms. To date, 2 Arl8b effectors (SKIP and HOPS) have been discovered that in conjunction with Arl8b mediate lysosome motility and trafficking (Fig.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…20,24 Arl8 localization as well as its function in regulating lysosome positioning and trafficking has since been found to be conserved across evolution. 23,25,33,34 Arl8 is distinct from the other Arf proteins (but similar to the Arls) in that it lacks a conserved glycine residue at the second position crucial for myristoylation-a post-translational lipid modification required for membrane targeting of all Arf proteins. 11 The glycine residue is replaced by leucine in case of Arl8b, and by isoleucine in case of Arl8a, rendering the human Arl8 proteins as potential substrates for N-acetyl transferase complex C (NatC).…”

Section: Introductionmentioning

confidence: 99%

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Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology

Khatter¹,

Sindhwani

Sharma³

2015

Cellular Logistics

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“…In vitro culture of coelomocytes was performed as previously described (30). The isolated coelomocytes were incubated in 150 μL medium (Gibco, #18045-088) containing TMR-dextran (100 μg/mL, 70,000 M r ) in a glass-bottom dish (Iwaki) for 20 min at 20°C.…”

Section: Methodsmentioning

confidence: 99%

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

Maekawa

Shimpei²,

Mochizuki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

113

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Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and solutes are internalized into cells. Macropinocytosis starts with the formation of membrane ruffles at the plasma membrane and ends with their closure. The transient and sequential emergence of phosphoinositides PI(3,4,5)P 3 and PI(3,4) P 2 in the membrane ruffles is essential for macropinocytosis. By making use of information in the Caenorhabditis elegans mutants defective in fluid-phase endocytosis, we found that mammalian phosphoinositide phosphatase MTMR6 that dephosphorylates PI(3)P to PI, and its binding partner MTMR9, are required for macropinocytosis. INPP4B, which dephosphorylates PI(3,4)P 2 to PI(3)P, was also found to be essential for macropinocytosis. These phosphatases operate after the formation of membrane ruffles to complete macropinocytosis. Finally, we showed that KCa3.1, a Ca 2+ -activated K + channel that is activated by PI(3)P, is required for macropinocytosis. We propose that the sequential breakdown of PI(3,4,5)P 3 → PI(3,4)P 2 → PI(3)P → PI controls macropinocytosis through specific effectors of the intermediate phosphoinositides.

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The Arf-like GTPase Arl8 Mediates Delivery of Endocytosed Macromolecules to Lysosomes inCaenorhabditis elegans

Abstract: Late endosomes and lysosomes directly fuse for content mixing to form hybrid organelles. In the present study, we show that the Caenorhabditis elegans ARL-8 GTPase is localized primarily to lysosomes and involved in late endosome-lysosome fusion in the macrophage-like coelomocytes.

Cited by 77 publications

References 55 publications

MHC Class II Presentation Is Controlled by the Lysosomal Small GTPase, Arl8b

MHC Class II Presentation Is Controlled by the Lysosomal Small GTPase, Arl8b

Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis

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