Localization and projected role of phosphatidylinositol 4-kinases IIα and IIβ in inositol 1,4,5-trisphosphate-sensitive nucleoplasmic Ca²⁺store vesicles

Abstract

Phosphatidylinositol (PI) kinases are key molecules that participate in the phosphoinositide signaling in the cytoplasm. Despite the accumulating evidence that supports the existence and operation of independent PI signaling system in the nucleus, the exact location of the PI kinases inside the nucleus is not well defined. Here we show that PI4-kinases IIα and IIβ, which play central roles in PI(4,5)P2 synthesis and PI signaling, are localized in numerous small nucleoplasmic vesicles that function as inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-sensitive Ca2+ stores. This is in accord with the past results that showed the localization of PI4(P)5-kinases that are essential in PI(4,5)P2 production and PI(4,5)P2 in nuclear matrix. Along with PI(4,5)P2 that also exists on the nucleoplasmic vesicle membranes, the localization of PI4-kinases IIα and IIβ in the nucleoplasmic vesicles strongly implicates the vesicles to the PI signaling as well as the Ins(1,4,5)P3-depenent Ca2+ signaling in the nucleus. Accordingly, the nucleoplasmic vesicles indeed release Ca2+ rapidly in response to Ins(1,4,5)P3. Further, the Ins(1,4,5)P3-induced Ca2+ release studies suggest that PI4KIIα and IIβ are localized near the Ins(1,4,5)P3 receptor (Ins(1,4,5)P3R)/Ca2+ channels on the Ca2+ store vesicle membranes. In view of the widespread presence of the Ins(1,4,5)P3-dependent Ca2+ store vesicles and the need to fine-control the nuclear Ca2+ concentrations at multiple sites along the chromatin fibers in the nucleus, the existence of the key PI enzymes in the Ins(1,4,5)P3-dependent nucleoplasmic Ca2+ store vesicles appears to be in perfect harmony with the physiological roles of the PI kinases in the nucleus.

Nuclear phosphatidylinositol 4,5-bisphosphate islets contribute to efficient RNA polymerase II-dependent transcription

“…Until now, the only known nuclear subcompartments containing PtdIns(4,5)P 2 were nucleoplasmic vesicles, which serve as the storage nuclear domain for Ca 2+ and might be involved in transcription via Ca 2+ -regulated chromatin remodelling in bovine adrenal chromaffin cells (Yoo et al, 2014). Even though these subcompartments are similar to NLIs in size (50 nm), they are enclosed by a membrane.…”

Nuclear Phosphoinositides: Their Regulation and Roles in Nuclear Functions

“…Nuclear substrates phosphorylated by PKC include lamins, topoisomerase1 and DNA polymerase [71,72,73,74,75,76]. Ins(1,4,5) P 3 binds to Ins(1,4,5)P 3 receptors present on the inner nuclear envelope [77] as well as on nuclear lipid bodies [78] to release calcium directly into the nucleus [77,79,80,81,82]. Increased nuclear calcium modulates calcium-calmodulin dependent protein kinases to regulate transcription [83].…”

Plasma membrane processes are differentially regulated by type I phosphatidylinositol phosphate 5-kinases and RASSF4

“…Several phosphoinositide kinases have been identified in the nucleus, including PIP5KIα, PIP5KIγi4, PIPKIIα and PIPKIIβ (Tan et al, 2015). PtdIns(4,5)P 2 has been identified on nucleoplasmic calcium storage vesicles that also include PIP4KIIα and PIP4KIIβ and InsP 3 receptors (Yoo et al, 2014). Interestingly, nuclear PIP5KIα has been found to reduce cancer risk by stabilizing p53 via interaction with heat shock proteins.…”