Palmitoylation of phospholipid scramblase 1 controls its distribution between nucleus and plasma membrane.
Phospholipid scramblase 1 (PLSCR1) is a Ca(2+)-binding, endofacial plasma membrane protein thought to contribute to the transbilayer movement of phosphatidylserine and other membrane phospholipids that is observed upon influx of calcium into the cytosol. Expression of PLSCR1 is markedly induced by interferon and other cytokines, and PLSCR1-/- bone marrow cells exhibit defective myeloid proliferation and differentiation in response to stimulation by select growth factors, implying that PLSCR1 also functions in cytokine signaling or response pathways. PLSCR1 is multiply palmitoylated and partitions into membrane lipid raft domains. We have now identified the Cys-rich sequence (184)CCCPCC(189) in PLSCR1 as required for palmitoylation of the polypeptide. Mutation of these five cysteines abrogates PLSCR1 trafficking to the plasma membrane and results in virtually all of the expressed protein localizing to the nucleus. Consistent with this observation, cell treatment with the palmitoylation inhibitor, 2-bromo-palmitate, results in a marked redistribution of endogenous PLSCR1 from plasma membrane to nucleus. In a small percentage of untreated cells, predominantly nuclear localization of PLSCR1 is also observed. Furthermore, PLSCR1 is also found in the nucleus following its cytokine-induced expression. These data suggest that under the circumstance of rapid biosynthesis in response to gene induction by cytokines, PLSCR1 traffics into the nucleus, implying a potential nuclear function for this protein.
Wiedmer
Therese
T
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Zhao
Ji
J
Nanjundan
Meera
M
Sims
Peter J
PJ
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D000941:Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D016207:Cytokines / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010168:Palmitates / Q000494:pharmacology; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000941:Antigens; D002352:Carrier Proteins; D016207:Cytokines; D008565:Membrane Proteins; D010168:Palmitates; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; C022776:2-bromopalmitate; D019308:Palmitic Acid; D003545:Cysteine