Abstract
Phosphoinositide membrane signaling is critical for normal physiology, playing well-known roles in diverse human pathologies. The basic mechanisms governing phosphoinositide signaling within the nucleus, however, have remained deeply enigmatic owing to their presence outside the nuclear membranes. Over 40% of nuclear phosphoinositides can exist in this non-membrane state, held soluble in the nucleoplasm by nuclear proteins that remain largely unidentified. Recently, two nuclear proteins responsible for solubilizing phosphoinositides were identified, steroidogenic factor-1 (SF-1; NR5A1) and liver receptor homolog-1 (LRH-1; NR5A2), along with two enzymes that directly remodel these phosphoinositide/protein complexes, phosphatase and tensin homolog (PTEN; MMAC) and inositol polyphosphate multikinase (IPMK; ipk2). These new footholds now permit the assignment of physiological functions for nuclear phosphoinositides in human diseases, such as endometriosis, nonalcoholic fatty liver disease/steatohepatitis, glioblastoma, and hepatocellular carcinoma. The unique nature of nuclear phosphoinositide signaling affords extraordinary clinical opportunities for new biomarkers, diagnostics, and therapeutics. Thus, phosphoinositide biology within the nucleus may represent the next generation of low-hanging fruit for new drugs, not unlike what has occurred for membrane phosphatidylinositol 3-kinase drug development. This review connects recent basic science discoveries in nuclear phosphoinositide signaling to clinical pathologies, with the hope of inspiring development of new therapies.
Highlights
Nuclear receptor mammalian physiologyBefore delving into the interesting signaling properties of these nuclear receptors, it is worthwhile to introduce the mammalian physiology controlled by this class of transcription factors
Phosphoinositide membrane signaling is critical for normal physiology, playing well-known roles in diverse human pathologies
We showed that the complex of steroidogenic factor-1 (SF-1) bound by phosphoinositides is a direct substrate for the phosphoinositide signaling enzymes, phosphatase and tensin homolog (PTEN) and inositol polyphosphate multikinase (IPMK) (Fig. 3) [1]
Summary
Before delving into the interesting signaling properties of these nuclear receptors, it is worthwhile to introduce the mammalian physiology controlled by this class of transcription factors. Recent studies using viruses to acutely rescue Lrh-1 in liverspecific knockout mice have physiologically linked Lrh-1 with arachidonic acid metabolism and several other aspects of lipid homeostasis in the liver [75] Both Sf-1 and Lrh-1 are downregulated by posttranslational modification with the small ubiquitin-like modifier (SUMO), and several elegant knock-in studies, which generated “SUMO-less” Sf-1 and Lrh-1 mice, have shown that SUMO physiologically regulates the activities of both Sf-1 [76] and Lrh-1 [77,78,79,80]. Both SF-1 [13] and LRH-1 [55] bind the signaling phosphoinositides, PI[4,5]P2 and PI[3,4,5]P3, with nanomolar affinity [14, 57]
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