title: Phosphatidylinositol 4,5-Bisphosphate Homeostasis Regulated by Nir2 and Nir3 Proteins at Endoplasmic Reticulum-Plasma Membrane Junctions.
abstract: Phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) at the plasma membrane (PM) constitutively controls many cellular functions, and its hydrolysis via receptor stimulation governs cell signaling. The PI transfer protein Nir2 is essential for replenishing PM PIP2 following receptor-induced hydrolysis, but key mechanistic aspects of this process remain elusive. Here, we demonstrate that PI at the membrane of the endoplasmic reticulum (ER) is required for the rapid replenishment of PM PIP2 mediated by Nir2. Nir2 detects PIP2 hydrolysis and translocates to ER-PM junctions via binding to phosphatidic acid. With distinct phosphatidic acid binding abilities and PI transfer protein activities, Nir2 and its homolog Nir3 differentially regulate PIP2 homeostasis in cells during intense receptor stimulation and in the resting state, respectively. Our study reveals that Nir2 and Nir3 work in tandem to achieve different levels of feedback based on the consumption of PM PIP2 and function at ER-PM junctions to mediate nonvesicular lipid transport between the ER and the PM.
authors.affiliation: From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Chi-Lun
authors.identifier: http://orcid.org/0000-0003-0017-2243
authors.initials: CL
authors.lastname: Chang
authors.affiliation: From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 jen.liou@utsouthwestern.edu.
authors.forename: Jen
authors.identifier: http://orcid.org/0000-0003-1546-3115
authors.initials: J
authors.lastname: Liou
mesh_terms: D002135:Calcium-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D005136:Eye Proteins / Q000032:analysis / Q000378:metabolism*; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D026901:Membrane Transport Proteins; D010712:Phosphatidic Acids / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000032:analysis / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D005136:Eye Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C113505:PITPNM1 protein, human; C117888:PITPNM2 protein, human; D010712:Phosphatidic Acids; D019269:Phosphatidylinositol 4,5-Diphosphate
keywords: endoplasmic reticulum (ER); lipid transport; phosphatidic acid; phosphatidylinositol; phosphatidylinositol signaling; phospholipid metabolism; plasma membrane; protein translocation; subcellular organelle