PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity
- 1Tokyo University of Science
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.
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BibTeX
@misc{kanemaru2026plcxd2,
title = {{PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity}},
author = {K. Kanemaru and W. Iwata and A. Katayanagi and F. Oka and Y. Kikuchi and N. Kono and H.-C. Lee-Okada and H. Osada and H. Kajiho and J. Hasegawa and S. Morioka and J. Sasaki and A. Hagiwara and N. Ban and J. Aoki and T. Yokomizo and T. Sasaki and Y. Nakamura},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.13.750855},
url = {https://www.biorxiv.org/content/10.64898/2026.09.13.750855v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity
AU - K. Kanemaru
AU - W. Iwata
AU - A. Katayanagi
AU - F. Oka
AU - Y. Kikuchi
AU - N. Kono
AU - H.-C. Lee-Okada
AU - H. Osada
AU - H. Kajiho
AU - J. Hasegawa
AU - S. Morioka
AU - J. Sasaki
AU - A. Hagiwara
AU - N. Ban
AU - J. Aoki
AU - T. Yokomizo
AU - T. Sasaki
AU - Y. Nakamura
PY - 2026
DA - 2026/09/13
PB - bioRxiv
DO - 10.64898/2026.09.13.750855
UR - https://www.biorxiv.org/content/10.64898/2026.09.13.750855v1
AB - 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.
ER -