Phosphatidylserine and RhoB connect PI4P and PA metabolism to maintain plasma membrane identity

  • J Cell Biol. 2026 Aug 3;225(8):e202509213. doi: 10.1083/jcb.202509213.
Shiying Huang  1  2 ,  Yeun Ju Kim  3 ,  Xiaofu Cao  1  2 ,  Timothy W Bumpus  1  2 ,  Mira Sohn  4 ,  Matthew Tyler Menold  4 ,  Ryan K Dale  4 ,  Jin Joo Kang  2  5 ,  Saori Uematsu  6 ,  Shagun Gupta  2  5 ,  Shu-Bing Qian  6 ,  Haiyuan Yu  2  5 ,  Tamas Balla  3 ,  Jeremy M Baskin  1  2
Affiliations
  • 1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
  • 2. Weill Institute for Cell and Molecular Biology, Cornell University , Ithaca, NY, USA.
  • 3. Section on Molecular Signal Transduction, NICHD, National Institutes of Health, Bethesda, MD, USA.
  • 4. Bioinformatics and Scientific Programming Core, NICHD, National Institutes of Health , Bethesda, MD, USA.
  • 5. Department of Computational Biology, Cornell University, Ithaca, NY, USA.
  • 6. Department of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
PMID: 42360433 DOI: 10.1083/jcb.202509213
Abstract

Proper functions of cellular organelles require tight control of membrane phospholipid composition, yet the mechanisms by which lipid imbalances are sensed and corrected remain largely unknown. Here, we present evidence of an unexpected metabolic connection between plasma membrane (PM) phosphoinositide metabolism and two key anionic lipids, phosphatidylserine (PS) and phosphatidic acid (PA). Prolonged depletion of PM phosphatidylinositol 4-phosphate (PI4P) by pharmacological inhibition of PI 4-kinase IIIα (PI4KIIIα/PI4KA) increases Phospholipase D (PLD) activity and PA levels in the PM. Using lipidomics, RNA-seq, and proximity proteomics, we find that PI4P loss induces a concomitant decrease in PS, activating a reciprocal relationship between PS synthesis and PLD-mediated PA generation. These changes also drive transcriptional and translational upregulation of the small GTPase RhoB, which enhances PLD-mediated PA synthesis and actin cytoskeletal remodeling. Because reduced PI4KA activity underlies numerous hereditary diseases, our studies reveal how perturbation of PM phosphoinositide synthesis triggers an integrated response that maintains the anionic character and structural integrity of the PM.

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