PLSCR1-/- mice exhibit normal, steady-state hematologic parameters but impaired emergency granulopoiesis upon in vivo administration of G-CSF. The mechanism by which PLSCR1 contributes to G-CSF-induced neutrophil production is largely unknown. We now report that the expansion of bone marrow myelocytes upon in vivo G-CSF treatment is reduced in PLSCR1-/- mice relative to WT. Using SCF-ER-Hoxb8-immortalized myeloid progenitors to examine the progression of G-CSF-driven granulocytic differentiation in vitro, we found that PLSCR1 prolongs the period of mitotic expansion of proliferative granulocyte precursors, thereby giving rise to increased neutrophil production from their progenitors. This effect of PLSCR1 is blocked by a ΔNLS-PLSCR1, which prevents its nuclear import. By contrast, mutation that prevents the membrane association of PLSCR1 has minimal impact on the role of PLSCR1 in G-CSF-induced granulopoiesis. These data imply that the capacity of PLSCR1 to augment G-CSF-dependent production of mature neutrophils from myeloid progenitors is unrelated to its reported activities at the endofacial surface of the plasma membrane but does require entry of the protein into the nucleus, suggesting that this response is mediated through the observed effects of PLSCR1 on gene transcription.
"Activities of scramblase 1 (PLS1) that are independent of lipid transfer have been found. PLS1 translocates to the nucleus and functions as a transcription factor with DNA binding ability (Chen et al., 2011a; Zhou et al., 2005). Modeling of PLS1 suggests that this and other PLS isoforms belong to the family of Tubby-like proteins that function as transcription factors (Bateman et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Historically, cellular trafficking of lipids has received much less attention than protein trafficking, mostly because its biological importance was underestimated, involved sorting and translocation mechanisms were not known, and analytical tools were limiting. This has changed during the last decade, and we discuss here some progress made in respect to mitochondria and the trafficking of phospholipids, in particular cardiolipin. Different membrane contact site or junction complexes and putative lipid transfer proteins for intra- and intermembrane lipid translocation have been described, involving mitochondrial inner and outer membrane, and the adjacent membranes of the endoplasmic reticulum. An image emerges how cardiolipin precursors, remodeling intermediates, mature cardiolipin and its oxidation products could migrate between membranes, and how this trafficking is involved in cardiolipin biosynthesis and cell signaling events. Particular emphasis in this review is given to mitochondrial nucleoside diphosphate kinase D and mitochondrial creatine kinases, which emerge to have roles in both, membrane junction formation and lipid transfer.
Chemistry and Physics of Lipids 12/2013; 179. DOI:10.1016/j.chemphyslip.2013.12.008 · 2.42 Impact Factor
"These results indicate that PLSCR1 is not required for FGF1 secretion from U937 cells. Although a strong correlation exists between FGF1 export and PLSCR1 expression in U937 cells, PLSCR1 has been shown to be neither sufficient nor necessary for PS externalization in live cells (Zhou et al., 2002), and it has other functions besides phospholipid translocation (Ben-Efraim et al., 2004; Chen et al., 2010). Thus, the acidic phospholipid transporter(s) involved in the nonclassical secretion of FGF1 have yet to be elucidated. "
[Show abstract][Hide abstract] ABSTRACT: The mechanisms of nonclassical export of signal peptide-less proteins remain insufficiently understood. Here, we demonstrate that stress-induced unconventional export of FGF1, a potent and ubiquitously expressed mitogenic and proangiogenic protein, is associated with and dependent on the formation of membrane blebs and localized cell surface exposure of phosphatidylserine (PS). In addition, we found that the differentiation of promonocytic cells results in massive FGF1 release, which also correlates with membrane blebbing and exposure of PS. These findings indicate that the externalization of acidic phospholipids could be used as a pharmacological target to regulate the availability of FGF1 in the organism.
[Show abstract][Hide abstract] ABSTRACT: Importin α1 can bind classical nuclear localization signals (NLSs) in two NLS-binding sites, known as “major” and “minor.” The major site is located between
ARM repeats 2–4, whereas the minor site spans ARM 7–8. In this study, we have characterized the cellular localization of human
phospholipid scramblase 4 (hPLSCR4), a member of the phospholipid scramblase protein family. We identified a minimal NLS in
hPLSCR4 (273GSIIRKWN280) that contains only two basic amino acids. This NLS is both necessary for nuclear localization of hPLSCR4 in transfected
HeLa cells and sufficient for nuclear import of a non-diffusible cargo in permeabilized cells. Mutation of only one of the
two basic residues, Arg277, correlates with loss of nuclear localization, suggesting this amino acid plays a key role in nuclear transport. Crystallographic
analysis of mammalian importin α1 in complex with the hPLSCR4-NLS reveals this minimal NLS binds specifically and exclusively
to the minor binding site of importin α. These data provide the first structural and functional evidence of a novel NLS-binding
mode in importin α1 that uses only the minor groove as the exclusive site for nuclear import of nonclassical cargos.
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