β4-Galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development

Nishie, Toshikazu; Hikimochi, Yoko; Zama, Kota; Fukusumi, Yoshiyasu; Ito, Mitutoshi; Yokoyama, Haruhiko; Naruse, Chie; Ito, Makoto; Asano, Masahide

doi:10.1093/glycob/cwq098

Cited by 60 publications

(44 citation statements)

References 49 publications

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“…A lack of GalT5 was shown to induce accumulation of GlcCer. 25 Therefore, accumulation of renal GlcCer in LN mice may be, in part, because of decreased GalT5 expression.…”

Section: Discussionmentioning

confidence: 99%

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Nowling

Mather²,

Thiyagarajan

et al. 2015

Journal of the American Society of Nephrology

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Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

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“…A lack of GalT5 was shown to induce accumulation of GlcCer. 25 Therefore, accumulation of renal GlcCer in LN mice may be, in part, because of decreased GalT5 expression.…”

Section: Discussionmentioning

confidence: 99%

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Nowling

Mather²,

Thiyagarajan

et al. 2015

Journal of the American Society of Nephrology

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“…In contrast, KO of B4galt5 resulted in severe defects in development, indicating that β1,4Gal-T5 might be the main LacCer synthase (Kumagai et al 2009 ;Nishie et al 2010 ). The phenotype resulting from disruption of the LacCer synthase was similar to that induced by KO of GlcCer synthase.…”

Section: Laccer Synthase Ko Micementioning

confidence: 86%

Glycosphingolipids in the Regulation of the Nervous System

Ohmi

Ohkawa

Tajima

et al. 2014

Advances in Neurobiology

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The highest expression of gangliosides, sialic acid-containing glycosphingolipids (GSLs), is found in the nervous tissue of vertebrates. Changes in the profiles of gangliosides during the development of nervous tissues indicate that they are involved in the regulation of neurogenesis and synaptogenesis. Their distinct distribution patterns support the suggestion that they are involved in both the differentiation and function of neural cells. In addition to results of studies of GSLs done using biochemical, histopathological, and cell biological approaches, recent progress in the genetic engineering of glycosyltransferase genes has resulted in novel findings and concepts about their roles in the nervous system. Roles of GSLs in the regulation of signaling that determine cell fates in membrane microdomains such as lipid rafts have been extensively studied. In particular, gene targeting of glycosyltransferases in mice has enabled investigation of the in vivo functions of GSLs. The majority of abnormal phenotypes exhibited by knockout (KO) mice may reflect an abnormal structure and a resultant altered function of lipid rafts caused by alterations in their GSL composition. Generally speaking, abnormal phenotypes found in most KO mice were milder than expected, suggesting that the remaining GSLs compensate for the functions of those lost. There are also functions that cannot be replaced by the remaining GSLs. Thus, there may be two modes of function of GSLs: one is nonspecific and can be carried out by multiple GSLs, the second mode is that in which the function of the missing GSL(s) cannot be compensated by others. Identification of natural ligands for individual GSLs is crucial in order to clarify the functions of each structure.

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“…If a factor like GABPI is required for membrane-linked activity is still not known. There are, however, two mammalian homologs of b4GalNAcTB that can transfer galactose to glucosylceramide [14,19,20]. These enzymes are b4GalT5 and -6, and at least b4GalT5 can do this only when membrane bound [29].…”

Section: Discussionmentioning

confidence: 99%

"Add-on" domains of Drosophila β1,4-N-acetylgalactosaminyltransferase B in the stem region and its pilot protein

Kraft

Johswich²,

Kauczor

et al. 2011

Cell. Mol. Life Sci.

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The glycolipid specific Drosophila melanogaster β1,4-N-acetylgalactosaminyltransferase B (β4GalNAcTB) depends on a zinc finger DHHC protein family member named GalNAcTB pilot (GABPI) for activity and translocation to the Golgi. The six-membrane spanning protein actually lacks the cysteine in the cytoplasmic DHHC motif, displaying DHHS instead. Here we show that the whole conserved region around the DHHS sequence, which is essential for palmitoylation in DHHC proteins, is not required for GABPI to interact with β4GalNAcTB. In contrast, the two luminal loops between transmembrane domain 3-4 and 5-6 contain conserved amino acids, which are crucial for activity. Besides the dependence on GABPI, β4GalNAcTB requires its exceptional short stem region for activity. A few hydrophobic amino acids positioned close to the transmembrane domain are essential for the interaction with GABPI. Along with its catalytic domain, β4GalNAcTB, thus, requires an area in its own stem region and two small luminal loops of GABPI as "add-on" domains. Moreover, some inactive GABPI mutants could be rescued by fusion with β4GalNAcTB, indicating their importance in direct GABPI-β4GalNAcTB interaction.

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β4-Galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development

Cited by 60 publications

References 49 publications

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Glycosphingolipids in the Regulation of the Nervous System

"Add-on" domains of Drosophila β1,4-N-acetylgalactosaminyltransferase B in the stem region and its pilot protein

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