9.01.2006

IP6 and mRNA Export

See this entry for background on inositols. Inositol-6-phosphate (aka Inositol hexaphosphate, phytic acid, phytate) is a strange compound.

Apparently plants make loads of it, and it is thought that they use this molecule to store phosphate. Also it would seem that lots of cancer researchers have been throwing this compound onto oncogenic cell lines. Apparently IP6 works to inhibit cell growth ... but as to it's effectiveness in vivo, I don't know. Phytate is also sold as a dietary supplement. But lets talk about its known cellular functions. Now it turns out that IP6 is a co-factor required for mRNA export.

mRNA export is a strange field. Some background ... mRNA is synthesized in the nucleus and then exported to the cytoplasm where it is translated into protein. It was originally thought that mRNA utilized karyopherins and the Ran cycle to get exported from the nucleus (click here for more on nuclear transport), but it turned out that mRNA used its very own transport machinery. In vertebrates, UAP56 is recruited to the mRNA during transcription. Then during splicing, a second factor Aly associates with UAP56. Finally Aly recruits a heterodimer of TAP and NXT1 which have to ability to interact with components of the Nuclear Pore Complex (NPC)and thus facilitate nuclear export. Now obviously mRNA export must be powered by an energy utilizing process. Enter Dbp5, an RNA helicase that is situated in the NPC. Helicases are enzymes that use ATP derived energy to walk along DNA or RNA chains (conceptually similar to a myosin motor using ATP to walk along an actin filament). As the helicase move along the DNA/RNA it acts to either separate double stranded nucleic acid chains or strip off proteins that are bound to the single stranded RNA. OK a simple story. Dbp5 is a motor that drags mRNA out of the nucleus and strips off all these factors that got it to the NPC in the first place.

Now some weird stuff. In yeast, Inositol kinases mutants had mRNA export defects. As I explained a couple of days ago, many Inositol derivatives act as signalling molecules. So what gives? Well it turns out that Dbp5 requires IP6 as a co-factor. This small molecule stimulates Dbp5's helicase activity and it's ability to bind to NPC components such as Gle1. This is illuatrated in this diagram from a recent review:

nuclearexport.jpg

Now why would IP6 be involved in mRNA export? There must be something big behind this. And I'm sure we will get more information soon. But it sounds like IP6 could act as a regulatory molecule ... want to bump up mRNA export? Make IP6. Want to turn it off? Degrade IP6. Now when and why global mRNA export should be regulated is completely unknown, but that's also true of 90% of cellular behavior ...

ref:
Cole CN, Scarcelli JJ. Related Articles, Links
Transport of messenger RNA from the nucleus to the cytoplasm.
Curr Opin Cell Biol. (2006) 18:299-306.

Weirich CS, Erzberger JP, Flick JS, Berger JM, Thorner J, Weis K.
Activation of the DExD/H-box protein Dbp5 by the nuclear-pore protein Gle1 and its coactivator InsP6 is required for mRNA export.
Nat Cell Biol. (2006) 8:668-76


Alcazar-Roman AR, Tran EJ, Guo S, Wente SR
Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export.
Nat Cell Biol. (2006) 8:711-6.

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