PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity
Year: 2026
Type: preprint
Abstract: 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.
Institutions: Tokyo University of Science, Research Institute for Science and Technology, Tokyo University of Science, Institute of Science Tokyo, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo, Institute of Integrated Research, Institute of Science Tokyo, The University of Tokyo, Juntendo University, Keio University
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7213612378