Paranodal junction formation and spermatogenesis require sulfoglycolipids

Honke, Koichi; Hirahara, Yukie; Dupree, Jeffrey L.; Suzuki, Kinuko; Popko, Brian; Fukushima, Kunihiro; Fukushima, Junko; Nagasawa, Takashi; Yoshida, Nobuaki; Wada, Yoshinao; Taniguchi, Naoyuki

doi:10.1073/pnas.032068299

Cited by 308 publications

(316 citation statements)

References 27 publications

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“…Furthermore, elevated levels of lactosylceramides with the concomitant reduction of gangliosides may alter plasma membrane organization and cellular activities, as described in refs. 29-31. Deletion of members of the gala-series of glycosphingolipids, which include galacosylceramide and sulfatide, produce mice with phenotypes remarkably similar to the double-null Galgt1 Siat9 mice (16,32). Furthermore, these glycolipids play key roles in axonal-glia interactions and in formation of the node of Ranvier (33).…”

Section: Discussionmentioning

confidence: 99%

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Yamashita

Wu²,

Sandhoff³

et al. 2005

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

211

160

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Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia.glycosphingolipid ͉ neurodegeneration ͉ glycosyltransferase

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Section: Discussionmentioning

confidence: 99%

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Yamashita

Wu²,

Sandhoff³

et al. 2005

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

211

160

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“…We reported the requirement of Drosophila ␤1,4-galactosyltransferase I, which contributes to the synthesis of the linkage structure of proteoglycans, for viability (21). However, we did not investigate whether the lethality of the sll RNAi fly is caused by a reduction in the sulfation of proteoglycans or other sulfated glycoconjugates, such as sulfatides (40) and HNK-1 epitope (41). As shown in Fig.…”

Section: Fig 2 Subcellular Localization Of Papst1 Proteinmentioning

confidence: 99%

Molecular Cloning and Identification of 3′-Phosphoadenosine 5′-Phosphosulfate Transporter

Kamiyama

Suda

Ueda

et al. 2003

Journal of Biological Chemistry

124

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Nucleotide sulfate, namely 3 -phosphoadenosine 5 -phosphosulfate (PAPS), is a universal sulfuryl donor for sulfation. Although a specific PAPS transporter is present in Golgi membrane, no study has reported the corresponding gene. We have identified a novel human gene encoding a PAPS transporter, which we have named PAPST1, and the Drosophila melanogaster ortholog, slalom (sll). The amino acid sequence of PAPST1 (432 amino acids) exhibited 48.1% identity with SLL (465 amino acids), and hydropathy analysis predicted the two to be type III transmembrane proteins. The transient expression of PAPST1 in SW480 cells showed a subcellular localization in Golgi membrane. The expression of PAPST1 and SLL in yeast Saccharomyces cerevisiae significantly increased the transport of PAPS into the Golgi membrane fraction. In human tissues, PAPST1 is highly expressed in the placenta and pancreas and present at lower levels in the colon and heart. An RNA interference fly of sll produced with a GAL4-UAS system revealed that the PAPS transporter is essential for viability. It is well known that mutations of some genes related to PAPS synthesis are responsible for human inherited disorders. Our findings provide insights into the significance of PAPS transport and post-translational sulfation.Glycosylation, phosphorylation, and sulfation are essential post-translational alterations of glycoproteins, proteoglycans, and glycolipids for normal growth and development. For sulfation, an activated form of sulfate, 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS), 1 is used as a common sulfate donor (1). Sulfate is transferred from PAPS to a defined position on the sugar residue by sulfotransferases. In higher organisms, PAPS is synthesized in the cytosol (2, 3) by a bifunctional PAPS synthetase having both ATP-sulfurylase and adenosine-phosphosulfate kinase activities (4). Since sulfation occurs in the lumens of the endoplasmic reticulum and Golgi apparatus (5), PAPS must be translocated from the cytosol into the Golgi lumen through a specific transporter localized in the microsomal membrane.Earlier studies had shown a saturable transport activity of PAPS using isolated Golgi vesicles (6) or reconstituted proteoliposome (7). To identify this transporter protein, the proteins responsible for PAPS translocating activity have been purified (8 -10). The characterization of these purified proteins revealed the kinetic behavior of a PAPS-specific transport through an antiport mechanism (8 -10); however, cloning of the transporter has not been reported.Recently, several nucleotide-sugar transporters (NSTs) have been cloned and characterized in mammals, yeast, protozoa, and plants (11-13). Nucleotide-sugars are the donor substrates for glycosylation, which is catalyzed by glycosyltransferases. These NST proteins are highly hydrophobic Type III multitransmembrane proteins localized in the Golgi or endoplasmic reticulum membrane and provide a specific substrate for the glycosylation. The structural conservation among NSTs has contributed to the identifi...

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“…Several studies have proposed the biological functions of sulfatides in various fields, including the nervous system, immune system, glucose metabolism, osmotic regulation, spermatogenesis, thrombosis/hemostasis, microbial infection, and cancer [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

“…This reaction is catalyzed only by cerebroside sulfotransferase (CST) [3]. In contrast, sulfatides are degraded in this reverse reaction that is catalyzed by arylsulfatase A (ARSA) [1,2].…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

et al. 2012

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Sulfatides, 3-O-sulfogalactosylceramides, are known to have multifunctional properties. These molecules are distributed in various tissues of mammals, where they are synthesized from galactosylceramides by sulfation at C3 of the galactosyl residue.Although this reaction is specifically catalyzed by cerebroside sulfotransferase (CST), the mechanisms underlying the transcriptional regulation of this enzyme are not understood. With respect to this issue, we previously found potential sequences of peroxisome proliferator-activated receptor (PPAR) response element on upstream regions of the mouse CST gene and presumed the possible regulation by the nuclear receptor PPARα. To confirm this hypothesis, we treated wild-type and Ppara-null mice with the specific PPARα agonist fenofibrate and examined the amounts of sulfatides and CST gene expression in various tissues. Fenofibrate treatment increased sulfatides and CST mRNA levels in the kidney, heart, liver, and small intestine in a PPARα-dependent manner. However, these effects of fenofibrate were absent in the brain or colon.Fenofibrate treatment did not affect the mRNA level of arylsulfatase A, which is the key enzyme for catalyzing desulfation of sulfatides, in any of these six tissues. Analyses of the DNA-binding activity and conventional gene expression targets of PPARα has demonstrated that fenofibrate treatment activated PPARα in the kidney, heart, liver, and 4 small intestine but did not affect the brain or colon. These findings suggest that PPARα activation induces CST gene expression and enhances sulfatide synthesis in mice, which suggests that PPARα is a possible transcriptional regulator for the mouse CST gene.(less than 250 words)

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Paranodal junction formation and spermatogenesis require sulfoglycolipids

Cited by 308 publications

References 27 publications

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Molecular Cloning and Identification of 3′-Phosphoadenosine 5′-Phosphosulfate Transporter

Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

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