IP8: A quantitatively minor inositol pyrophosphate signaling molecule that punches above its weight

Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8

“…Although it is now widely appreciated that mammalian XPR1 mediates PP-IP-dependent regulation of Pi efflux from mammalian cells, it remains unclear if XPR1 is a genuine Pi-transport protein or a regulator of another Pi transporter. 18 This conundrum has limited our ability to further our molecular-level understanding of the regulation of Pi efflux from mammalian cells. Future application of methodologies to generate adequate levels of XPR1 in a mammalian expression system, then purify the protein to homogeneity, and incorporate it into phospholipid vesicles for Pi transport assays 19 could serve as an informative experimental platform to screen for potential ancillary factors that might be required to recapitulate the actions of fully functional XPR1 in vitro .…”

“…Nevertheless, it should be noted that Pi transport activity by XPR1 has not yet been directly validated (i.e., by reconstitution into liposomes), so it remains formally possible that this protein is instead a regulator of another, as yet unsuspected Pi transporter. 18 On the other hand, an XPR1 ortholog from rice, O sPHO1:2, which is also present in plasma membranes, has been incorporated into liposomes and shown to transport Pi. 19 The regulation of XPR1-dependent Pi transport activity is thought to be mediated by IP 8 binding to lysine surface cluster within the N-terminal SYG1/Pho81/XPR1 (SPX) domain of XPR1.…”

Proteome-wide quantification of inositol pyrophosphate-protein interactions

“…While 5PP-InsP5 appears to be the most abundant PP-InsP in many mammalian cell lines, 7,15 a few reports have invoked a signaling role for the closely related molecule 1PP-InsP5 43 . In addition, several recent studies have substantiated a unique signaling function for 1,5(PP)2-InsP4 34,35,44 .…”

“…In most human cell lines, InsP6 is quite abundant with a concentration range of 10 -50 µM 7 . PP-InsPs, by contrast, are less abundant and their levels have been estimated to be 1-5 µM for 5PP-InsP5, 0.1 -0.5 µM for 1,5(PP)2-InsP4, and 0.02 -0.1 µM for 1PP-InsP5 (Figure 1b) 44,57 .…”