Role of Nuclear Transport Factors in Interphase and Mitosis: from viral pathogenesis to cell division
My laboratory is studying the cell biology of constituents of the nuclear transport machinery. These proteins, which comprise nuclear pore complex proteins and their interacting transport factors, mediate the transport of molecules into and out of the nucleus. We focus on two areas, namely the role of these proteins in nuclear transport under both physiological and pathological conditions, and the role of these proteins during mitosis. Physiologic studies focus on the mechanisms of nuclear import and export, and pathological studies focus on how these processes are disrupted during viral infections. During mitosis, following nuclear envelope breakdown, these constituents of the nuclear transport machinery acquire new functions, and we are studying their roles as regulators of mitosis progression.
In interphase
Background. Signal-mediated nuclear import and export of molecules occurs through nuclear pore complexes (NPC). These are highly regulated pathways that control nuclear entry and exit of molecules such as transcription factors, RNAs, kinases and viral particles. Abnormal nuclear transport is associated with leukemogenesis and viral pathogenesis. In general, to be imported or exported from the nucleus, molecules 1) bind to transport receptors, 2) are transported through nuclear pore complexes (NPCs) present in the nuclear envelope, 3) and translocate from the NPC to intranuclear or cytoplasmic target sites. Although progress has been made regarding the composition and mechanisms of the nuclear transport machinery, less is known about the function and regulation of major constituents of the NPC. NPCs are composed of proteins termed nucleoporins or Nups, which play a role in the structure of the NPC and in regulating the translocation of molecules through the NPC.
Nuclear export in viral pathogenesis. We have previously identified and characterized two major Nups termed Nup98 and Nup96, which are encoded by the same gene, and we have also studied their interacting partners (J. Cell Biol. 1999; J. Biol. Chem. 2000; PNAS 2001; Mol. Cell Biol. 2003). Nup98 is a key regulator of nuclear entry and exit of proteins and nucleic acids. We found that the Nup98 interacting partner Rae1/mrnp41, an mRNA export factor, is a target of a viral protein that inhibits mRNA nuclear export (Science 2002; Mol Cell 2005). The vesicular stomatitis virus (VSV) matrix protein (M) binds Rae1. The inhibition of mRNA export induced by VSV M protein can be reverted by IFN-mediated increased expression of Nup98 and Rae1. Thus, the Nup98/Rae1 pathway regulates both nuclear export of mRNAs and, likely, antiviral response. We are currently investigating the role of Rae1 in viral replication at the cellular level and in whole animal models.
Mechanisms of nuclear transport and immune response. We have previously shown that Nup96 forms a complex with other nucleoporins and its immediate interacting partner is Sec13, which is also a constituent of the endoplasmic reticulum (J. Cell Biol. 1999; Mol. Cell Biol. 2003). Other groups reported these interactions in Xenopus and S. cerevisiae. Like Nup98, Nup96 is up-regulated by interferon (Science 2002). To investigate the function of Nup96, we have generated mice models, which show defects in immune response. Thus, we are currently studying the role of Nup96 in immunity.
In mitosis
In mitosis, when nuclear envelope breaks down, key constituents of the nuclear transport machinery assume additional functions, including regulation of spindle assembly and nuclear envelope re-assembly. For example, Ran and karyopherins were found to be key regulators of spindle assembly. RanGTP functions in mitosis as in interphase, except that the reactions take place in the absence of nuclear envelope. During mitosis and interphase, RanGTP releases proteins (cargos) from karyopherins. However, in mitosis, these cargos are key controllers of spindle assembly. These findings place the nuclear transport machinery at the very center of cell division. In addition, nuclear pore complexes are partially disassembled in mitosis and some Nups are found in sub-complexes at the kinetochores and spindles. One of the goals of my laboratory is to elucidate the role of key Nups in mitosis.
SIGNIFICANT PUBLICATIONS
Satterly, N. Tsai, P-L., van Deursen, J., Nussenzveig, D.R., Wang, Y., Faria, P.A., Levay, A., Levy, D.E., and B. M. A. Fontoura, "Influenza Virus Targets the mRNA Export Machinery and the Nuclear Pore Complex" PNAS, 104 (6):1853-1858, February 2007
Faria A.M., Levay A., Wang Y., Kamphorst A.O., Rosa M.L., Nussenzveig D.R., Balkan W., Chook Y.M., Levy D.E., and B.M.A. Fontoura, "The Nucleoporin Nup96 is Required for Proper Expression of Interferon-Regulated Proteins and Functions" Immunity, 24 (3):295-304, March 2006
Faria, P.A., Chakraborty, P., Levay, A., Barber, G.N., Ezelle, H., Enninga, J., Arana, C., van Deursen, J., and B. M. A. Fontoura, "VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway." Mol. Cell, 17:93-102, 2005
Enninga, J., Levay, A., and B.M.A. Fontoura, "Sec13 shuttles between the nucleus and the cytoplasm and stably interacts with Nup96 at the Nuclear Pore Complex." Mol Cell. Biol., 23:7271-7284, 2003
Enninga, J., Levy, D.E., Blobel, G., and B.M.A. Fontoura, "Role of nucleoporin induction in releasing an mRNA nuclear export block." Science, 295:1523-1525, 2002
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