Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate

Abstract

Preface The membrane lipid phosphatidylinositol(3,4,5)trisphosphate (PtdInsP3) regulates membrane receptor signalling in many cells, including immunoreceptor signalling. Here, we review recent data that have indicated essential functions for the soluble PtdInsP3 analogue inositol(1,3,4,5)tetrakisphosphate (InsP4) in T cell, B cell and neutrophil development and function. Decreased InsP4 production in immunocytes causes immunodeficiency in mice and might contribute to inflammatory vasculitis in Kawasaki disease in humans. InsP4-producing kinases could therefore provide attractive drug targets for inflammatory and infectious diseases.

IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice

“…The differences between SHIP-1 42,43,77 Clearly, more detailed mechanistic studies are needed to discern the respective contributions of Akt/mTORC1-dampening by IP 4 and other mechanisms to HSC control by Itpkb.…”

“…[35][36][37][38][39][40][41][42] In its best understood in vivo function, IP 4 dampens Akt-recruitment and activation as a soluble PIP 3 competitor, but it is unclear whether this is broadly relevant. 43 Among the 3 mammalian Itpks a/b/c, HSC only express Itpkb significantly. 36 Whether Itpkb has any function in HSC is unknown.…”

Inositol tetrakisphosphate limits NK cell effector functions by controlling PI3K signaling

“…[26][27][28][29][30][31][32] By catalyzing a similar chemical reaction to that of PI3K, ItpkB phosphorylates IP 3 into inositol(1,3,4,5)-tetrakisphosphate (IP 4 ). 33 As a soluble PIP 3 analog, IP 4 can bind to PH domains and either promote or inhibit PIP 3 binding. [26][27][28][29]33 Many PH domains bind PIP 3 and IP 4 with similar affinities.…”

“…33 As a soluble PIP 3 analog, IP 4 can bind to PH domains and either promote or inhibit PIP 3 binding. [26][27][28][29]33 Many PH domains bind PIP 3 and IP 4 with similar affinities. 19 A major open question is how many PI3K functions are regulated by IP 4 .…”

“…19 A major open question is how many PI3K functions are regulated by IP 4 . 33 Given the importance of PI3K in NK cell development and function, we assessed how ItpkB and thus IP 4 deficiency affect these processes. We found that ItpkB promotes NK cell terminal maturation and acquisition of a mature NKR repertoire.…”