The position of lysosomes within the cell determines their luminal pH

Johnson, Danielle; Ostrowski, Philip P.; Jaumouillé, Valentin; Grinstein, Sergio

doi:10.1083/jcb.201507112

Cited by 478 publications

(572 citation statements)

References 73 publications

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“…3G). The latter likely represent lysosomes that are less acidic, such as those described in the periphery of nonneuronal cells (40). We also observed more diffuse SEP fluorescence in the distal axon, including the growth cone ( Fig.…”

Section: Resultssupporting

confidence: 48%

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BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Farı́as

Guardia

Pace

et al. 2017

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

180

234

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The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show that an ensemble of BORC, Arl8, SKIP, and kinesin-1, previously shown to mediate centrifugal transport of lysosomes in nonneuronal cells, specifically drives lysosome transport into the axon, and not the dendrites, in cultured rat hippocampal neurons. This transport is essential for maintenance of axonal growth-cone dynamics and autophagosome turnover. Our findings illustrate how a general mechanism for lysosome dispersal in nonneuronal cells is adapted to drive polarized transport in neurons, and emphasize the importance of this mechanism for critical axonal processes.

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Section: Resultssupporting

confidence: 48%

“…3). This heterogeneity resembles that recently reported for lysosomes in nonneuronal cells (40). Lysosomes in the proximal and distal parts of the axon depend on the BORC-Arl8-SKIP-kinesin-1 complex for anterograde transport.…”

Section: Discussionmentioning

confidence: 47%

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Farı́as

Guardia

Pace

et al. 2017

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

180

234

View full text Add to dashboard Cite

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“…This suggests that the requirements for cell-to-cell fusion and virus-to-cell fusion are different. The luminal pH of most lysosomes ranges from 4.5 to 5 (45). In contrast, we utilized phosphate-buffered saline (PBS) at pH 4 in the cell-to-cell …”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization

Acciani

Alston

Zhao

et al. 2017

J Virol

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Lassa virus (LASV) is an enveloped RNA virus endemic to West Africa and responsible for severe cases of hemorrhagic fever. Virus entry is mediated by the glycoprotein complex consisting of a stable-signal peptide, a receptor-binding subunit, GP1, and a viral-host membrane fusion subunit, GP2. Several cellular receptors can interact with the GP1 subunit and mediate viral entry, including alpha-dystroglycan (␣DG) and lysosome-associated membrane protein 1 (LAMP1). In order to define the regions within GP1 that interact with the cellular receptors, we implemented insertional mutagenesis, carbohydrate shielding, and alanine scanning mutagenesis. Eighty GP constructs were engineered and evaluated for GP1-GP2 processing, surface expression, and the ability to mediate cell-to-cell fusion after low-pH exposure. To examine virus-to-cell entry, 49 constructs were incorporated onto vesicular stomatitis virus (VSV) pseudoparticles and transduction efficiencies were monitored in HAP1 and HAP1-ΔDAG1 cells that differentially produce the ␣DG cell surface receptor. Seven constructs retained efficient transduction in HAP1-ΔDAG1 cells yet poorly transduced HAP1 cells, suggesting that they are involved in ␣DG utilization. Residues H141, N146, F147, and Y150 cluster at the predicted central core of the trimeric interface and are important for GP-␣DG interaction. Additionally, H92A-H93A, 150HA, 172HA, and 230HA displayed reduced transduction in both HAP1 and HAP1-ΔDAG1 cells, despite efficient cell-to-cell fusion activity. These mutations may interfere with interactions with the endosomal receptor LAMP1 or interfere at another stage in entry that is common to both cell lines. Insight gained from these data can aid in the development of more-effective entry inhibitors by blocking receptor interactions.IMPORTANCE Countries in which Lassa virus is endemic, such as Nigeria, Sierra Leone, Guinea, and Liberia, usually experience a seasonal outbreak of the virus from December to March. Currently, there is neither a preventative vaccine nor a therapeutic available to effectively treat severe Lassa fever. One way to thwart virus infection is to inhibit interaction with cellular receptors. It is known that the GP1 subunit of the Lassa glycoprotein complex plays a critical role in receptor recognition. Our results highlight a region within the Lassa virus GP1 protein that interacts with the cellular receptor alpha-dystroglycan. This information may be used for future development of new Lassa virus antivirals.

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“…A recent study has shown that juxtanuclear lysosomes are more acidic and have higher cathepsin L activity than peripheral lysosomes (Johnson et al, 2016). This heterogeneity could be due to the stabilization of the V-ATPase subunit V1G1 by RILP (Johnson et al, 2016).…”

Section: Autophagymentioning

confidence: 99%

Mechanisms and functions of lysosome positioning

Guardia

Keren-Kaplan

et al. 2016

Journal of Cell Science

424

466

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Lysosomes have been classically considered terminal degradative organelles, but in recent years they have been found to participate in many other cellular processes, including killing of intracellular pathogens, antigen presentation, plasma membrane repair, cell adhesion and migration, tumor invasion and metastasis, apoptotic cell death, metabolic signaling and gene regulation. In addition, lysosome dysfunction has been shown to underlie not only rare lysosome storage disorders but also more common diseases, such as cancer and neurodegeneration. The involvement of lysosomes in most of these processes is now known to depend on the ability of lysosomes to move throughout the cytoplasm. Here, we review recent findings on the mechanisms that mediate the motility and positioning of lysosomes, and the importance of lysosome dynamics for cell physiology and pathology.

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The position of lysosomes within the cell determines their luminal pH

Cited by 478 publications

References 73 publications

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization

Mechanisms and functions of lysosome positioning

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