Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport

Kobayashi, Toshihide; Beuchat, Marie-Hélène; Lindsay, Margaret; Frias, Sonia; Palmiter, Richard D.; Sakuraba, Hitoshi; Parton, Robert G.; Grüenberg, Jean

doi:10.1038/10084

Cited by 506 publications

(475 citation statements)

References 24 publications

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“…U18666A (Sigma) is an amphipathic steroid which is widely used to block the intracellular trafficking of cholesterol and mimic the Niemann-Pick type C disease phenotype (12,35). Cytotoxicity was tested using the CellTiter 96 nonradioactive cell proliferation assay (Promega) following the manufacturer=s instructions.…”

Section: Methodsmentioning

confidence: 99%

Cholesterol Flux Is Required for Endosomal Progression of African Swine Fever Virions during the Initial Establishment of Infection

Cuesta-Geijo

Chiappi

Galindo

et al. 2016

J Virol

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African swine fever virus (ASFV) is a major threat for porcine production that has been slowly spreading in Eastern Europe since its first appearance in the Caucasus in 2007. ASFV enters the cell by endocytosis and gains access to the cytosol to start replication from late endosomes and multivesicular bodies. Cholesterol associated with low-density lipoproteins entering the cell by endocytosis also follows a trafficking pathway similar to that of ASFV. Here we show that cholesterol plays an essential role in the establishment of infection as the virus traffics through the endocytic pathway. In contrast to the case for other DNA viruses, such as vaccinia virus or adenovirus 5, cholesterol efflux from endosomes is required for ASFV release/entry to the cytosol. Accumulation of cholesterol in endosomes impairs fusion, resulting in retention of virions inside endosomes. ASFV also remodels intracellular cholesterol by increasing its cellular uptake and redistributes free cholesterol to viral replication sites. Our analysis reveals that ASFV manipulates cholesterol dynamics to ensure an appropriate lipid flux to establish productive infection. IMPORTANCESince its appearance in the Caucasus in 2007, African swine fever (ASF) has been spreading westwards to neighboring European countries, threatening porcine production. Due to the lack of an effective vaccine, ASF control relies on early diagnosis and widespread culling of infected animals. We investigated early stages of ASFV infection to identify potential cellular targets for therapeutic intervention against ASF. The virus enters the cell by endocytosis, and soon thereafter, viral decapsidation occurs in the acid pH of late endosomes. We found that ASFV infection requires and reorganizes the cellular lipid cholesterol. ASFV requires cholesterol to exit the endosome to gain access to the cytoplasm to establish productive replication. Our results indicate that there is a differential requirement for cholesterol efflux for vaccinia virus or adenovirus 5 compared to ASFV.

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Section: Methodsmentioning

confidence: 99%

Cholesterol Flux Is Required for Endosomal Progression of African Swine Fever Virions during the Initial Establishment of Infection

Cuesta-Geijo

Chiappi

Galindo

et al. 2016

J Virol

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“…The epitope-tagged ZnT-2 is localized on acidic vesicles, and overexpression of ZnT-2 facilitates the accumulation of zinc into the vesicles in high zinc conditions [96]. Later, the vesicles with a highly vacuolated appearance were shown to be late endosomes [109]. Taken together, ZnT-2 functions as a zinc transporter to sequester zinc into endosomes.…”

Section: Review Articlementioning

confidence: 97%

Overview of mammalian zinc transporters

Kambe

Yamaguchi-Iwai

Sasaki

et al. 2004

Cellular and Molecular Life Sciences (CMLS)

356

285

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In recent years, a number of mammalian zinc transporters have been identified, and candidate genes are rapidly growing. These transporters are classified into two families: ZIP (ZRT, IRT-like protein) and CDF (cation diffusion facilitator). ZIP members facilitate zinc influx into the cytosol, while CDF members facilitate its efflux from the cytosol. Molecular characterization of the transporters has brought about major advances in our understanding of their physiological functions. Zinc metabolism is regulated primarily through zinc-dependent control of transcription, translation, and intracellular trafficking of transporters. Analyses of mice whose zinc transporter genes have been genetically disrupted and of the naturally occurring mutant mice with symptoms related to abnormal zinc metabolism have provided compelling evidence that some zinc transporters play critical roles in zinc homeostasis. In this review, we review the literature of mammalian zinc transporters with emphasis on very recent findings and elicit integrative knowledge of zinc homeostasis.

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“…Therefore, it is possible that the normal NPC1 + vesicle regulates cholesterol transport through a 'kiss-and-run' cycle with lysosomes, and that U18666A and progesterone disrupt the fission of NPC1+ vesicles from the lysosome. Furthermore, the compartment in which cholesterol accumulates in both U18666A-treated and NP-C cells is enriched with the unique lipid, lysobisphosphatidic acid (LBPA) [54]. LBPA is found only in the core of these vesicles, and treatment with U18666A alters the ultrastructural appearance of this domain.…”

Section: Sequence Homology and Similar Pharmacology Suggest A Functiomentioning

confidence: 99%

The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly

Incardona

Roelink

2000

CMLS, Cell. Mol. Life Sci.

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Holoprosencephaly, or an undivided forebrain, is a complex brain malformation associated with Sonic hedgehog (Shh) mutations. Other causes of holoprosencephaly have converged upon the Shh signaling pathway: genetic and pharmacologic impairment of cholesterol synthesis, and the action of the steroidal alkaloid cyclopamine. This review focuses on recent studies aimed at determining how Shh signaling is affected by these causes of holoprosencephaly, whether they involve a common mechanism and the role played by cholesterol. Cholesterol is potentially important for both biogenesis of Shh and in signal transduction in Shh-responsive cells. Teratogens that induce holoprosencephaly appear to affect Shh signal transduction rather than Shh biogenesis. Analysis of these agents and other compounds that affect various aspects of cellular cholesterol distribution indicates that the role of cholesterol in Shh signal transduction is novel and complicated. The similarity of the Shh receptor, Patched (Ptc), to the Niemann-Pick Cl protein, which is involved in the vesicular trafficking of cholesterol, provides insight into the role of cholesterol and the action of compounds like cyclopamine.

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Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport

Cited by 506 publications

References 24 publications

Cholesterol Flux Is Required for Endosomal Progression of African Swine Fever Virions during the Initial Establishment of Infection

Cholesterol Flux Is Required for Endosomal Progression of African Swine Fever Virions during the Initial Establishment of Infection

Overview of mammalian zinc transporters

The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly

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