Ablation of Vacuole Protein Sorting 18 (Vps18) Gene Leads to Neurodegeneration and Impaired Neuronal Migration by Disrupting Multiple Vesicle Transport Pathways to Lysosomes

Peng, Chao; Ye, Jian; Yan, Shunfei; Kong, Shanshan; Ye, Shen; Li, Chenyu; Li, Qinyu; Zheng, Yufang; Deng, Kejing; Xu, Tian; Tao, Wufan

doi:10.1074/jbc.m112.384305

Cited by 38 publications

(42 citation statements)

References 48 publications

(68 reference statements)

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“…Both multivesicular bodies and autophagosomes were increased, suggesting that the endocytic pathway and autophagic flux are both affected due to the loss of VPS18. 10 However, in bf mice, the endocytic pathway and lysosomal functions are apparently normal. The point mutation in VPS33A D251E did not alter its protein's stability or subcellular localization.…”

Section: Discussionmentioning

confidence: 99%

“…This explains why bf mice are viable and less severely affected whereas the Vps18 ¡/¡ mice are not viable. 9,10 Inferred from the crystal structure of C. thermophilum VPS33, the D251 residue is localized in the domain 3a region, which is predicted as the interacting interface between VPS33 and syntaxins. 26 Our results support that the D251-containing domain 3a likely mediates the direct interaction with STX17.…”

Section: Discussionmentioning

confidence: 99%

“…For example, lack of VPS18 caused the disruption of autophagy, endocytosis, and lysosomal function. 10 We therefore tested whether the endocytic pathway and lysosomal function in bf mice are affected. EGFR (epidermal growth factor receptor) is a typical cargo protein that is transported to the lysosomes through the endocytic pathway.…”

Section: The Endocytic Pathway and Lysosome Function Are Normal In Bfmentioning

confidence: 99%

“…Defects in neuronal migration resulted from the upregulation of ITGB1/b1 integrin. 10 The bf mutant was identified as a Hermansky-Pudlak syndrome model, exhibiting hypopigmentation, and platelet storage pool deficiency. 9 It has been reported that motor deficits and Purkinje neuronal loss exist in bf mice.…”

Section: Introductionmentioning

confidence: 99%

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Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33A^D251E mutation

Zhen

2015

Autophagy

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-associated membrane protein 1; LRO, lysosome-related organelle; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MEF, mouse embryonic fibroblast; RFP, red fluorescent protein; SNARE, soluble Nethylmaleimide-sensitive attachment protein (SNAP) receptor; SQSTM1/p62, sequestosome 1; STX, syntaxin; TH, tyrosine hydroxylase; VAMP, vesicle associated membrane protein/synaptobrevin; VPS, vacuole protein sorting; WT, wild type.The HOPS (homotypic fusion and protein sorting) complex functions in endocytic and autophagic pathways in both lower eukaryotes and mammalian cells through its involvement in fusion events between endosomes and lysosomes or autophagosomes and lysosomes. However, the differential molecular mechanisms underlying these fusion processes are largely unknown. Buff (bf) is a mouse mutant that carries an Asp251-to-Glu point mutation (D251E) in the VPS33A protein, a tethering protein and a core subunit of the HOPS complex. Bf mice showed impaired spontaneous locomotor activity, motor learning, and autophagic activity. Although the gross anatomy of the brain was apparently normal, the number of Purkinje cells was significantly reduced. Furthermore, we found that fusion between autophagosomes and lysosomes was defective in bf cells without compromising the endocytic pathway. The direct association of mutant VPS33A D251E with the autophagic SNARE complex, STX17 (syntaxin 17)-VAMP8-SNAP29, was enhanced. In addition, the VPS33A D251E mutation enhanced interactions with other HOPS subunits, namely VPS41, VPS39, VPS18, and VPS11, except for VPS16. Reduction of the interactions between VPS33A Y440D and several other HOPS subunits led to decreased association with STX17. These results suggest that the VPS33A D251E mutation plays dual roles by increasing the HOPS complex assembly and its association with the autophagic SNARE complex, which selectively affects the autophagosome-lysosome fusion that impairs basal autophagic activity and induces Purkinje cell loss.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Endocytic Pathway and Lysosome Function Are Normal In Bfmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33A^D251E mutation

Zhen

2015

Autophagy

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“…Tissue processing and frozen section and immunofluorescent microscopic analysis were performed as described elsewhere (30). The analysis for infiltration foci was described previously (31).…”

Section: Histologymentioning

confidence: 99%

Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

Shi

et al. 2014

The Journal of Immunology

Self Cite

119

126

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Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1−/− mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1−/− bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency–mediated human immunodeficiency syndrome.

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Cortical Neuron Migration in Health and Disease

Javier‐Torrent,

Nguyen

2023

Neocortical Neurogenesis in Development and Evolution

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Ablation of Vacuole Protein Sorting 18 (Vps18) Gene Leads to Neurodegeneration and Impaired Neuronal Migration by Disrupting Multiple Vesicle Transport Pathways to Lysosomes

Cited by 38 publications

References 48 publications

Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33A^D251E mutation

Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33A^D251E mutation

Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

Cortical Neuron Migration in Health and Disease

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Ablation of Vacuole Protein Sorting 18 (Vps18) Gene Leads to Neurodegeneration and Impaired Neuronal Migration by Disrupting Multiple Vesicle Transport Pathways to Lysosomes

Cited by 38 publications

References 48 publications

Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33AD251E mutation

Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33AD251E mutation

Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

Cortical Neuron Migration in Health and Disease

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Product

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Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33A^D251E mutation

Impairment of autophagosome-lysosome fusion in the buff mutant mice with the VPS33A^D251E mutation