Quantitative transcriptomic profiling of branching in a glycosphingolipid biosynthetic pathway

Hiromu Takematsu, Harumi Yamamoto, Yuko Naito-Matsui, Reiko Fujinawa, Kouji Tanaka, Yasushi Okuno, Yoshimasa Tanaka, Mamoru Kyogashima, Reiji Kannagi, Yasunori Kozutsumi

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9 Citations (Scopus)

Abstract

Cellular biosynthesis of macromolecules often involves highly branched enzyme pathways, thus cellular regulation of such pathways could be rather difficult. To understand the regulatory mechanism, a systematic approach could be useful. We genetically analyzed a branched biosynthetic pathway for glycosphingolipid (GSL) GM1 using correlation index-based responsible enzyme gene screening (CIRES), a novel quantitative phenotype- genotype correlation analysis. CIRES utilizes transcriptomic profiles obtained from multiple cells. Among a panel of B cell lines, expression of GM1 was negatively correlated with and suppressed by gene expression of CD77 synthase (CD77Syn), whereas no significant positive correlation was found for enzymes actually biosynthesizing GM1. Unexpectedly, a GM1-suppressive phenotype was also observed in the expression of catalytically inactive CD77Syn, ruling out catalytic consumption of lactosylceramide (LacCer) as the main cause for such negative regulation. Rather, CD77Syn seemed to limit other branching reaction(s) by targeting LacCer synthase (LacCer-Syn), a proximal enzyme in the pathway, because they were closely localized in the Golgi apparatus and formed a complex. Moreover, turnover of LacCerSyn was accelerated upon CD77Syn expression to globally change the GSL species expressed. Collectively, these data suggest that transcriptomic assessment of macromolecule biosynthetic pathways can disclose a global regulatory mechanism(s) even when unexpected.

Original languageEnglish
Pages (from-to)27214-27224
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number31
DOIs
Publication statusPublished - 05-08-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Takematsu, H., Yamamoto, H., Naito-Matsui, Y., Fujinawa, R., Tanaka, K., Okuno, Y., Tanaka, Y., Kyogashima, M., Kannagi, R., & Kozutsumi, Y. (2011). Quantitative transcriptomic profiling of branching in a glycosphingolipid biosynthetic pathway. Journal of Biological Chemistry, 286(31), 27214-27224. https://doi.org/10.1074/jbc.M111.234526