Brain-specific transcript variants of 5′ and 3′ ends of mouse VPS13A and VPS13C

Mizuno, Emiko; Nakamura, Masayuki; Agemura, Asumi; Kusumoto, Akira; Ichiba, Mio; Kurano, Yutaka; Muroya, Shinji; Sano, Akira

doi:10.1016/j.bbrc.2006.12.122

Cited by 14 publications

(9 citation statements)

References 9 publications

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“…The Vps13 protein contains two well-defined domains (Conserved Domains database, CDD NCBI): the N-terminal Chorein_N domain, which is proposed to form a leucine zipper for oligomerization or protein-protein interactions (41); and the SHR_BD (SHR-binding domain; previously known as DUF1162). SHR_BD is present in SHRUBBY (At5g24740), a vacuolar sorting protein of A. thaliana (42).…”

Section: Resultsmentioning

confidence: 99%

Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate

Rzepnikowska

Flis

Kamińska

et al. 2017

Human Molecular Genetics

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The rare human disorder chorea-acanthocytosis (ChAc) is caused by mutations in hVPS13A gene. The hVps13A protein interacts with actin and regulates the level of phosphatidylinositol 4-phosphate (PI4P) in the membranes of neuronal cells. Yeast Vps13 is involved in vacuolar protein transport and, like hVps13A, participates in PI4P metabolism. Vps13 proteins are conserved in eukaryotes, but their molecular function remains unknown. One of the mutations found in ChAc patients causes amino acids substitution I2771R which affects the localization of hVps13A in skeletal muscles. To dissect the mechanism of pathogenesis of I2771R, we created and analyzed a yeast strain carrying the equivalent mutation. Here we show that in yeast, substitution I2749R causes dysfunction of Vps13 protein in endocytosis and vacuolar transport, although the level of the protein is not affected, suggesting loss of function. We also show that Vps13, like hVps13A, influences actin cytoskeleton organization and binds actin in immunoprecipitation experiments. Vps13-I2749R binds actin, but does not function in the actin cytoskeleton organization. Moreover, we show that Vps13 binds phospholipids, especially phosphatidylinositol 3-phosphate (PI3P), via its SHR_BD and APT1 domains. Substitution I2749R attenuates this ability. Finally, the localization of Vps13-GFP is altered when cellular levels of PI3P are decreased indicating its trafficking within the endosomal membrane system. These results suggest that PI3P regulates the functioning of Vps13, both in protein trafficking and actin cytoskeleton organization. Attenuation of PI3P-binding ability in the mutant hVps13A protein may be one of the reasons for its mislocalization and disrupted function in cells of patients suffering from ChAc.

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Section: Resultsmentioning

confidence: 99%

Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate

Rzepnikowska

Flis

Kamińska

et al. 2017

Human Molecular Genetics

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“…Neither VPS13A n or SFI1 have been implicated in glioma formation. However, Vps13A is expressed in the mouse brain (44), and Sfi1 has been shown to induce G2 arrest in Saccharomyces cerevisiae (45). …”

Section: Discussionmentioning

confidence: 99%

Sleeping Beauty–Mediated Somatic Mutagenesis Implicates CSF1 in the Formation of High-Grade Astrocytomas

et al. 2010

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The Sleeping Beauty (SB) transposon system has been used as an insertional mutagenesis tool to identify novel cancer genes. To identify glioma-associated genes, we evaluated tumor formation in the brain tissue from 117 transgenic mice that had undergone constitutive SB-mediated transposition. Upon analysis, 21 samples (18%) contained neoplastic tissue with features of high-grade astrocytomas. These tumors expressed glial markers and were histologically similar to human glioma. Genomic DNA from SB-induced astrocytoma tissue was extracted and transposon insertion sites were identified. Insertions in the growth factor gene Csf1 were found in 13 of the 21 tumors (62%), clustered in introns 5 and 8. Using reverse transcription-PCR, we documented increased Csf1 RNAs in tumor versus adjacent normal tissue, with the identification of transposon-terminated Csf1 mRNAs in astrocytomas with SB insertions in intron 8. Analysis of human glioblastomas revealed increased levels of Csf1 RNA and protein. Together, these results indicate that SB-insertional mutagenesis can identify high-grade astrocytoma-associated genes and they imply an important role for CSF1 in the development of these tumors. Cancer Res; 70(9); 3557-65. ©2010 AACR.

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“…Vps13 is most similar in the amino acid sequence to hVps13A and contains several domains: Chorein_N, VPS13 domain, VPS13_mid_rpt, SHR_BD (previously called DUF1162, domain of unknown function No. 1162, Figure A) and VPS13_C; according to the Pfam database (http://pfam.xfam.org; Accessed July 28, 2017) . The ATG_C (autophagy‐related protein C‐terminal domain) region was recognized in yeast Vps13 and human Vps13A .…”

Section: Yeast As a Model To Study Vps13 Proteinsmentioning

confidence: 99%

Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

Rzepnikowska

Flis

Muñoz-Braceras

et al. 2017

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Human Vps13 proteins are associated with several diseases, including the neurodegenerative disorder Chorea-acanthocytosis (ChAc), yet the biology of these proteins is still poorly understood. Studies in Saccharomyces cerevisiae, Dictyostelium discoideum, Tetrahymena thermophila and Drosophila melanogaster point to the involvement of Vps13 in cytoskeleton organization, vesicular trafficking, autophagy, phagocytosis, endocytosis, proteostasis, sporulation and mitochondrial functioning. Recent findings show that yeast Vps13 binds to phosphatidylinositol lipids via 4 different regions and functions at membrane contact sites, enlarging the list of Vps13 functions. This review describes the great potential of simple eukaryotes to decipher disease mechanisms in higher organisms and highlights novel insights into the pathological role of Vps13 towards ChAc.

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Brain-specific transcript variants of 5′ and 3′ ends of mouse VPS13A and VPS13C

Cited by 14 publications

References 9 publications

Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate

Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate

Sleeping Beauty–Mediated Somatic Mutagenesis Implicates CSF1 in the Formation of High-Grade Astrocytomas

Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease

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