Kajiho, H. | bioRxiv Science

bioRxiv2026

PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity

PLCXD proteins have been linked to phosphoinositide metabolism for more than a decade, and PLCXD2 activity has been associated with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] depletion, yet its preferred direct substrate has remained unresolved. Here, cellular lipidomics showed that catalytically active PLCXD2 reduced the major phosphatidylinositol (PI) 38:4 species, with more modest phosphoinositide changes and increased diacylglycerol (DAG) and phosphatidic acid (PA). Using recombinant PLCXD2 and acyl-chain-matched substrates, we found that PLCXD2 hydrolyzed PI substantially more efficiently than PI(4,5)P2 and most other phosphoinositides tested. In Plcxd2-deficient retina, PI abundance was preserved, whereas DAG and PA were reduced without broad changes in major membrane phospholipid classes. PLCXD2 loss was associated with early structural abnormalities at the photoreceptor-bipolar synaptic interface, followed by outer nuclear layer thinning and reduced electroretinographic a-wave responses. These findings identify PLCXD2 as a PI-preferring mammalian PLC and reveal an endogenous role in retinal lipid homeostasis and outer retinal integrity.

biochemistry↗

bioRxiv2026

PITPβ Drives JAK2 V617F-Mediated Myeloproliferative Neoplasms by Promoting PtdIns(3,4)P2-Dependent AKT Hyperactivation

JAK2 is a key regulator of cytokine-mediated proliferative signaling in hematopoietic stem and progenitor cells. Activating mutations, most commonly JAK2 V617F, trigger aberrant cytokine signaling driving the pathogenesis of myeloproliferative neoplasms (MPNs). Phosphatidylinositol transfer proteins (PITPs) facilitate phosphoinositide synthesis by delivering phosphatidylinositol to lipid kinases, though their roles in oncogenic signaling have remained poorly defined. Here we show that PITP{beta} is critical for the development of JAK2V617F-driven MPN in mice. Deleting Pitp{beta} across the hematopoietic system, but not Pitp, prolonged 25-week survival of Jak2V617F mice from 10% to 85%. Loss of Pitp{beta} attenuated disease-associated splenomegaly and curtailed erythroid progenitors expansion both in vivo and in vitro. Mechanistically, PITP{beta} is necessary for AKT hyperactivation in hematopoietic progenitors, while STAT5 and ERK signaling remain unaffected. In alignment with this role, PITP{beta} promotes the production of PtdIns(3,4)P2, a phosphoinositide that sustains aberrant AKT signaling in Jak2V617F progenitors. Pharmacologic inhibition of AKT with the FDA-approved inhibitor capivasertib in Jak2V617F-transplanted mice similarly reduced splenomegaly and erythroid proliferation, mimicking the effects of Pitp{beta} loss. Collectively, these results identify a novel PITP{beta}-PtdIns(3,4)P2 signaling axis that selectively maintains pathological AKT activation in JAK2V617F-driven MPN, revealing a promising therapeutic vulnerability.

cancer biology↗