ITPK1 mediates the lipid-independent synthesis of inositol phosphates controlled by metabolism

Author:

Desfougères YannORCID,Wilson Miranda S. C.,Laha Debabrata,Miller Gregory J.,Saiardi AdolfoORCID

Abstract

Inositol phosphates (IPs) comprise a network of phosphorylated molecules that play multiple signaling roles in eukaryotes. IPs synthesis is believed to originate with IP3generated from PIP2by phospholipase C (PLC). Here, we report that in mammalian cells PLC-generated IPs are rapidly recycled to inositol, and uncover the enzymology behind an alternative “soluble” route to synthesis of IPs. Inositol tetrakisphosphate 1-kinase 1 (ITPK1)—found in Asgard archaea, social amoeba, plants, and animals—phosphorylates I(3)P1originating from glucose-6-phosphate, and I(1)P1generated from sphingolipids, to enable synthesis of IP6. We also found using PAGE mass assay that metabolic blockage by phosphate starvation surprisingly increased IP6levels in a ITPK1-dependent manner, establishing a route to IP6controlled by cellular metabolic status, that is not detectable by traditional [3H]-inositol labeling. The presence of ITPK1 in archaeal clades thought to define eukaryogenesis indicates that IPs had functional roles before the appearance of the eukaryote.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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