Defective lysosomal exocytosis and plasma membrane repair in Chediak–Higashi/beige cells

Huynh, Chau; Roth, Doris; Ward, Diane McVey; Kaplan, Jerry; Andrews, Norma W.

doi:10.1073/pnas.0405905101

Cited by 132 publications

(106 citation statements)

References 32 publications

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“…However, MHCII molecules may recycle through an early endosomal compartment dependent on the homologous fusion of early endosomes controlled by Rab5 so that the lack of Rab5 activity may lead to default delivery to late endosomes and then by normal endolysosomal Rab7-dependent maturation mechanisms to the lysosomes. Because Bg cells show defective trafficking to the late endosomal compartments and increased ability of these lysosomes to fuse with the plasma membrane (42,43), the loss of Nef-mediated MHCII down-regulation in Bg cells can perhaps be explained either by enhanced recycling back to the cell surface from early endosomes and/or by fusion of Bg lysosomes with the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef Promotes Endocytosis of Cell Surface MHC Class II Molecules via a Constitutive Pathway

Chaudhry

Verghese²,

Das³

et al. 2009

The Journal of Immunology

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HIV-1 Nef has been reported to disrupt MHC class II (MHCII)-mediated Ag presentation by a dual strategy that comprises a reduction in cell surface levels of peptide-loaded mature MHCII molecules and a up-regulation of immature MHCII molecules. We show that Nef achieves relocation of MHCII away from the cell surface in monocytic cells by both delaying its transport to the cell surface and by accelerating endocytic removal of cell surface MHCII to a lysosomal compartment. Nef-induced MHCII endocytosis is cholesterol-sensitive but clathrin- and dynamin-independent. Internalized MHCII molecules traverse the early endosomal system and colocalize with pinocytic cargo before reaching lysosomes. Nef-triggered MHCII endocytosis requires Rab5 activity and lyst function, whereas lysosomal trafficking of internalized MHCII molecules requires Rab7 activity. We further show that a similar pathway can remove peptide-MHCII complexes from the surface of monocytic cells not expressing Nef. Our data suggest that Nef uses mechanisms involved in normal MHCII recycling and turnover to mediate the delivery of cell surface MHCII to a lysosomal destination. Thus, Nef-mediated endocytosis of MHCII provides a novel perspective on the regulation of normal MHCII trafficking.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Nef Promotes Endocytosis of Cell Surface MHC Class II Molecules via a Constitutive Pathway

Chaudhry

Verghese²,

Das³

et al. 2009

The Journal of Immunology

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“…The expression of dominant-negative constructs or the genetic ablation of Syt VII results in impaired lysosomal exocytosis (6,10,11), and in marked alterations in the lysosomal secretion pattern (12). Previous studies using cells defective in lysosomal-regulatory proteins, such as the LYST protein that carries the mutation leading to enlarged lysosomes in ChediakHigashi/beige syndrome (13), showed that similar secretory defects are found in fibroblast conventional lysosomes (14) and in CTL lytic granules (15). Given that exocytosis of conventional lysosomes is also impaired in fibroblasts from Syt VII-deficient mice (10,11), we investigated whether a similar functional defect was present in CTLs from these animals.…”

Section: A Ctivated Cd8mentioning

confidence: 97%

Expression and Function of Synaptotagmin VII in CTLs

Fowler

Andrews

Huleatt

2007

The Journal of Immunology

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The Ca2+ sensor synaptotagmin (Syt) VII regulates the exocytosis of conventional lysosomes in several cell types. In CTLs, the Ca2+-regulated exocytosis of lytic granules/secretory lysosomes is responsible for the perforin/granzyme-mediated lysis of target cells. To investigate the role of Syt VII in CTL effector function, the expression and function of Syt VII were examined in wild-type and Syt VII-deficient mice. In comparison with Syt VII+/+ controls, Syt VII−/− animals were impaired in their ability to clear an infection with the intracellular pathogen Listeria monocytogenes. When isolated CTLs were examined, we found that Syt VII is expressed upon CTL activation and localizes to granzyme A-containing lytic granules. Syt VII-deficient CTLs have no defects in proliferation and cytokine production, and their lytic granules contain normal amounts of perforin and granzyme A and polarize normally at the immunological synapse. However, despite normal conjugate formation with target cells, CTLs from Syt VII−/− mice exhibit reduced effector activity, when compared with controls. Treatment of Syt VII+/+ or Syt VII−/− CTLs with an inhibitor of the perforin-mediated lytic pathway resulted in comparable levels of cytotoxic activity, suggesting that Syt VII regulates perforin-mediated cytolytic CTL responses.

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“…In specialized cells, such as cytotoxic T cells from CHS patients, lysosomes formed during differentiation are enlarged and are not secreted upon stimulation, although their content is apparently normal (Baetz et al, 1995). Non-specialized CHS cells also present enlarged lysosomes, which fail to fuse efficiently with the cell surface in response to membrane lesions (Huynh et al, 2004). The gene mutated in patients with CHS encodes a protein named lysosomal trafficking regulator or LYST (previously known as CHS1 in human and beige in mouse) (Barbosa et al, 1996;Nagle et al, 1996;Perou et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

A LYST/beige homolog is involved in biogenesis ofDictyosteliumsecretory lysosomes

Charette

Cosson

2007

Journal of Cell Science

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Chediak-Higashi syndrome (CHS) is characterized at the cellular level by a defect in the ability of cells to secrete lysosomes. However, the precise step affected in the secretion process is unclear. We characterized Dictyostelium discoideum cells containing a mutation in lvsB, the homolog of the human gene (LYST) involved in CHS. As observed in mammalian cells, secretion of lysosome-derived compartments was affected in lvsB mutant cells. This defect was mirrored by a decrease in the number of fusion-competent post-lysosomal compartments, which in Dictyostelium can be clearly distinguished from lysosomes. In addition, the transfer of endocytosed particles from lysosomes to post lysosomes was strongly diminished in lvsB mutant cells compared with the wild type. These results suggest that LvsB is primarily involved in transport from lysosomes to post lysosomes, and thus plays a critical role in the maturation of lysosomes into fusion-competent post-lysosomal compartments

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Defective lysosomal exocytosis and plasma membrane repair in Chediak–Higashi/beige cells

Cited by 132 publications

References 32 publications

HIV-1 Nef Promotes Endocytosis of Cell Surface MHC Class II Molecules via a Constitutive Pathway

HIV-1 Nef Promotes Endocytosis of Cell Surface MHC Class II Molecules via a Constitutive Pathway

Expression and Function of Synaptotagmin VII in CTLs

A LYST/beige homolog is involved in biogenesis ofDictyosteliumsecretory lysosomes

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