A Phospholipase C-Dependent Inositol Polyphosphate Kinase Pathway Required for Efficient Messenger RNA Export

Abstract

In order to identify additional factors required for nuclear export of messenger RNA, a genetic screen was conducted with a yeast mutant deficient in a factor Gle1p, which associates with the nuclear pore complex (NPC). The three genes identified encode phospholipase C and two potential inositol polyphosphate kinases. Together, these constitute a signaling pathway from phosphatidylinositol 4, 5-bisphosphate to inositol hexakisphosphate (IP6). The common downstream effects of mutations in each component were deficiencies in IP6 synthesis and messenger RNA export, indicating a role for IP6 in GLE1 function and messenger RNA export.

Inositol polyphosphate multikinase (ArgRIII) determines nuclear mRNA export inSaccharomyces cerevisiae

“…Inositol phosphates and the regulation of nuclear mRNA export Recently, York et al [5] described a mutant strain of yeast, named gsl3, that displayed changes in inositol phosphate turnover that, in some cases, are similar to those of our ipmkv strain. These include decreases in levels of InsP 6 , accompanied by increases in levels of InsP 2 , Ins(1,4,5)P 3 and InsP 4 [5].…”

“…Inositol phosphates and the regulation of nuclear mRNA export Recently, York et al [5] described a mutant strain of yeast, named gsl3, that displayed changes in inositol phosphate turnover that, in some cases, are similar to those of our ipmkv strain. These include decreases in levels of InsP 6 , accompanied by increases in levels of InsP 2 , Ins(1,4,5)P 3 and InsP 4 [5]. The protein product that was disrupted in the gsl3 strain was not identi¢ed, although it was suggested that it might be either (i) a regulator of kinase activities against InsP 3 and InsP 4 , or (ii) a multifunctional InsP 3 /InsP 4 kinase [5].…”

“…2, Table 1), presumably re£ecting some dephosphorylation of the excess Ins(1,4,5)P 3 . In yeasts, Ins(1,4,5)P 3 has been proposed to be a precursor for the synthesis of InsP 5 and InsP 6 [5,16]. This hypothesis is supported by the observations that, relative to the wild-type yeast, the ipmkv strain contained 100-fold lower levels of InsP 6 , and at least 10-fold lower levels of D/L-Ins(1,2,4,5,6)P 5 and Ins(1,3,4,5,6)P 5 (Fig.…”

“…In the latter investigation, three S. cerevisiae genes were identi¢ed which, when deleted, resulted in decreased e¤ciency of mRNA export from the nucleus via the nuclear pore complex [5]. In one of these mutant yeast strains, named gsl3, the de¢ciency in mRNA export was accompanied by a block in the pathway of InsP 6 synthesis, at the stages at which both InsP 3 and InsP 4 are phosphorylated [5].…”

Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited

“…In yeast, IP 6 affects mRNA export from the nucleus. 107 Another possibility is that higher order InsPs directly change gene promoter activity. In yeast, the genes encoding inositol synthase (ino-1) and the phosphate response gene pho5 are regulated through changes in ATPdependent chromatin remodeling complexes.…”