Nuclear import of exogenous FGF1 requires the ER-protein LRRC59 and the importins Kpnα1 and Kpnβ1.
Fibroblast growth factor 1 (FGF1) taken up by cells into endocytic vesicles can be translocated across vesicular membranes into the cytosol and the nucleus where it has a growth regulatory activity. Previously, leucine-rich repeat containing 59 (LRRC59) was identified as an intracellular binding partner of FGF1, but its biological role remained unknown. Here, we show that LRRC59 is strictly required for nuclear import of exogenous FGF1. siRNA-mediated depletion of LRRC59 did not inhibit the translocation of FGF1 into cytosol, but blocked the nuclear import of FGF1. We also found that an nuclear localization sequence (NLS) in FGF1, Ran GTPase, karyopherin-α1 (Kpnα1), and Kpnβ1 were required for nuclear import of FGF1. Nuclear import of exogenous FGF2, which depends on CEP57/Translokin, was independent of LRRC59, but was dependent on Kpnα1 and Kpnβ1, while the nuclear import of FGF1 was independent of CEP57. LRRC59 is a membrane-anchored protein that localizes to the endoplasmic reticulum (ER) and the nuclear envelope (NE). We found that LRRC59 possesses NLS-like sequences in its cytosolic part that can mediate nuclear import of soluble LRRC59 variants, and that the localization of LRRC59 to the NE depends on Kpnβ1. We propose that LRRC59 facilitates transport of cytosolic FGF1 through nuclear pores by interaction with Kpns and movement of LRRC59 along the ER and NE membranes.
Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, 0310, Norway.
Yan
Y
Zhen
Vigdis
V
Sørensen
Camilla S
CS
Skjerpen
Ellen M
EM
Haugsten
Yixin
Y
Jin
Sebastien
S
Wälchli
Sjur
S
Olsnes
Antoni
A
Wiedlocha
D021581:Active Transport, Cell Nucleus; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D009685:Nuclear Envelope / Q000378:metabolism; D019913:Nuclear Localization Signals; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D028901:alpha Karyopherins / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000378:metabolism
C423142:KPNA1 protein, human; C424166:KPNB1 protein, human; C574205:LRRC59 protein, human; D008565:Membrane Proteins; D019913:Nuclear Localization Signals; D034741:RNA, Small Interfering; D028901:alpha Karyopherins; D028961:beta Karyopherins; D016220:Fibroblast Growth Factor 1; D051745:Protein Kinase C-delta; D020931:ran GTP-Binding Protein