The Inositol-3-Phosphate Synthase Biosynthetic Enzyme Has Distinct Catalytic and Metabolic Roles. / Frej, Anna; Clark, jonathan; Le Roy, Caroline; Lilla, Sergio ; Thomason, Peter ; Otto, Grant; Churchill, Grant; Insall, Robert ; Claus, Sandrine; Hawkins, Phil; Stephens, Len; Williams, Robin.

In: Molecular and Cellular Biology, Vol. 36, No. 10, 02.05.2016, p. 1464-1479.

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  • Anna Frej
  • jonathan Clark
  • Caroline Le Roy
  • Sergio Lilla
  • Peter Thomason
  • Grant Otto
  • Grant Churchill
  • Robert Insall
  • Sandrine Claus
  • Phil Hawkins
  • Len Stephens
  • Robin Williams

Abstract

Inositol levels, maintained by the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), are altered in a range of disorders, including bipolar disorder and Alzheimer's disease. To date, most inositol studies have focused on the molecular and cellular effects of inositol depletion without considering Ino1 levels. Here we employ a simple eukaryote, Dictyostelium discoideum, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in an inositol auxotrophy that can be rescued only partially by exogenous inositol. Removal of inositol supplementation from the ino1− mutant resulted in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis, and substrate adhesion. Inositol depletion also caused a dramatic generalized decrease in phosphoinositide levels that was rescued by inositol supplementation. However, loss of Ino1 triggered broad metabolic changes consistent with the induction of a catabolic state that was not rescued by inositol supplementation. These data suggest a metabolic role for Ino1 that is independent of inositol biosynthesis. To characterize this role, an Ino1 binding partner containing SEL1L1 domains (Q54IX5) and having homology to mammalian macromolecular complex adaptor proteins was identified. Our findings therefore identify a new role for Ino1, independent of inositol biosynthesis, with broad effects on cell metabolism.
Original languageEnglish
Pages (from-to)1464-1479
Number of pages16
JournalMolecular and Cellular Biology
Volume36
Issue number10
Early online date2 May 2016
DOIs
Publication statusE-pub ahead of print - 2 May 2016
This open access research output is licenced under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

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