Susan R. Wente, Ph.D.
Vice Chancellor for Academic Affairs
Professor of Cell and Developmental Biology
205 Kirkland Hall
Nashville, TN 37240
Our goal is to understand the mechanism for highly selective, bidirectional exchange of proteins and RNA between the nucleus and cytoplasm. Nucleocytoplasmic trafficking is essential for cell function, and precisely regulated during cell division, differentiation and death. At the center of the transport mechanism are the nuclear pore complexes (NPCs), large protein machines embedded in the nuclear envelope and the only known sites for nuclear entry and exit. We use yeast, cultured human cells, and zebrafish model systems to address three broad questions.
(1) How are NPCs assembled? At least 30 different proteins associate in a nuclear envelope pore to form an NPC. Using genetic strategies and GFP-tagged NPCs, we are identifying assembly factors and monitoring NPC dynamics in live cells.
(2) How do proteins and genetic material move through the NPC? By genetic, molecular and biochemical means, we are investigating the mechanism by which transport factors utilize NPC proteins for movement. Studies also focus on elucidating steps in mRNA export, coupling between mRNA export and translation, and roles for inositol polyphosphate signaling in regulating transport.
(3) How do mRNA export and mRNP processing factors regulate vertebrate development and disease? Using the zebrafish model system and mammalian cell culture, we have defined mechanisms of pathogenesis that open up entirely new areas of investigation.
These basic projects impact human disease in several ways. In higher eukaryotes, proper NPC assembly is required for cell division and for maintaining transport, particularly in rapidly dividing cells (e.g. cancer cells). Cancer cells can also alter gene expression by perturbing nuclear transport. During viral infections, nuclear transport factors and NPC protein functions are inhibited or exploited to mediate viral RNA export. Recently, we demonstrated that an embryonic lethal form of human motor neuron disease also results from disregulation of mRNA export. We predict that elucidation of the mechanisms for NPC assembly, translocation and regulation will uncover other pathogenic mechanisms and identify druggable targets for controlling human disease. Overall, our future work will continue to integrate our discoveries from the analysis of single cell machineries into the context of multicellular organism development and pathophysiology.
- Burns, LT, Wente, SR Casein kinase II Regulation of the Hot1 Transcription Factor Promotes Stochastic Gene Expression. J Biol Chem, 2014.
- Burns, LT, Wente, SR From hypothesis to mechanism: Uncovering nuclear pore complex links to gene expression. Mol Cell Biol, 2014.
- Folkmann, AW, Dawson, TR, Wente, SR Insights into mRNA export-linked molecular mechanisms of human disease through a Gle1 structure-function analysis. Adv Biol Regul, 5474-91, 2014.
- Adams, RL, Terry, LJ, Wente, SR Nucleoporin FG Domains Facilitate mRNP Remodeling at the Cytoplasmic Face of the Nuclear Pore Complex. Genetics, 2014.
- Jao, LE, Wente, SR, Chen, W Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proc Natl Acad Sci U S A, 2013.
- Folkmann, AW, Collier, SE, Zhan, X, Aditi, , Ohi, MD, Wente, SR Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease. Cell, 155(3), 582-93, 2013.
- Natalizio, BJ, Wente, SR Postage for the messenger: designating routes for nuclear mRNA export. Trends Cell Biol, 2013.
- Adams, RL, Wente, SR Uncovering nuclear pore complexity with innovation. Cell, 152(6), 1218-21, 2013.
- Jao, LE, Appel, B, Wente, SR A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle1 function in spinal neural precursor survival and motor axon arborization. Development, 139(7), 1316-26, 2012.
- Casey, AK, Dawson, TR, Chen, J, Friederichs, JM, Jaspersen, SL, Wente, SR Integrity and function of the Saccharomyces cerevisiae spindle pole body depends on connections between the membrane proteins Ndc1, Rtn1, and Yop1. Genetics, 192(2), 441-55, 2012.
- Burns, LT, Wente, SR Nuclear GPS for Interchromosomal Clustering. Dev Cell, 22(6), 1119-20, 2012.
- Casey, AK, Wente, SR Nuclear transport: shifting gears in fungal nuclear and cytoplasmic organization. Curr Biol, 22(19), R846-8, 2012.
- Burns, LT, Wente, SR Trafficking to uncharted territory of the nuclear envelope. Curr Opin Cell Biol, 24(3), 341-9, 2012.
- Folkmann, AW, Noble, KN, Cole, CN, Wente, SR Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export. Nucleus, 2(6), 540-8, 2011.
- Bolger, TA, Wente, SR Gle1 is a multifunctional DEAD-box protein regulator that modulates Ded1 in translation initiation. J Biol Chem, 286(46), 39750-9, 2011.
- Wente, SR Spatial and temporal impacts on a career in science. Mol Biol Cell, 22(21), 3923-5, 2011.
- Hodge, CA, Tran, EJ, Noble, KN, Alcazar-Roman, AR, Ben-Yishay, R, Scarcelli, JJ, Folkmann, AW, Shav-Tal, Y, Wente, SR, Cole, CN The Dbp5 cycle at the nuclear pore complex during mRNA export I: dbp5 mutants with defects in RNA binding and ATP hydrolysis define key steps for Nup159 and Gle1. Genes Dev, 25(10), 1052-64, 2011.
- Noble, KN, Tran, EJ, Alcazar-Roman, AR, Hodge, CA, Cole, CN, Wente, SR The Dbp5 cycle at the nuclear pore complex during mRNA export II: nucleotide cycling and mRNP remodeling by Dbp5 are controlled by Nup159 and Gle1. Genes Dev, 25(10), 1065-77, 2011.
- Alcazar-Roman, AR, Bolger, TA, Wente, SR Control of mRNA export and translation termination by inositol hexakisphosphate requires specific interaction with Gle1. J Biol Chem, 285(22), 16683-92, 2010.
- Sarmah, B, Wente, SR Inositol hexakisphosphate kinase-2 acts as an effector of the vertebrate Hedgehog pathway. Proc Natl Acad Sci U S A, 107(46), 19921-6, 2010.
- Titus, LC, Dawson, TR, Rexer, DJ, Ryan, KJ, Wente, SR Members of the RSC chromatin-remodeling complex are required for maintaining proper nuclear envelope structure and pore complex localization. Mol Biol Cell, 21(6), 1072-87, 2010.
- Noble, KN, Wente, SR Nuclear mRNA on the move. Nat Cell Biol, 12(6), 525-7, 2010.
- Kelly, SM, Leung, SW, Apponi, LH, Bramley, AM, Tran, EJ, Chekanova, JA, Wente, SR, Corbett, AH Recognition of polyadenosine RNA by the zinc finger domain of nuclear poly(A) RNA binding protein 2 (Nab2) is required for correct mRNA 3''-end formation. J Biol Chem, 2010.
- Zheng, C, Fasken, MB, Marshall, NJ, Brockmann, C, Rubinson, ME, Wente, SR, Corbett, AH, Stewart, M Structural basis for the function of the Saccharomyces cerevisiae Gfd1 protein in mRNA nuclear export. J Biol Chem, 285(27), 20704-15, 2010.
- Carmody, SR, Tran, EJ, Apponi, LH, Corbett, AH, Wente, SR The mitogen-activated protein kinase Slt2 regulates nuclear retention of non-heat shock mRNAs during heat shock-induced stress. Mol Cell Biol, 30(21), 5168-79, 2010.
- Wente, SR, Rout, MP The nuclear pore complex and nuclear transport. Cold Spring Harb Perspect Biol, 2(10), a000562, 2010.
- Sarmah, B, Wente, SR Zebrafish inositol polyphosphate kinases: new effectors of cilia and developmental signaling. Adv Enzyme Regul, 50(1), 309-23, 2010.
- Hetzer, MW, Wente, SR Border control at the nucleus: biogenesis and organization of the nuclear membrane and pore complexes. Dev Cell, 17(5), 606-16, 2009.
- Sarmah, B, Wente, SR Dual functions for the Schizosaccharomyces pombe inositol kinase Ipk1 in nuclear mRNA export and polarized cell growth. Eukaryot Cell, 8(2), 134-46, 2009.
- Dawson, TR, Lazarus, MD, Hetzer, MW, Wente, SR ER membrane-bending proteins are necessary for de novo nuclear pore formation. J Cell Biol, 184(5), 659-75, 2009.
- Terry, LJ, Wente, SR Flexible gates: dynamic topologies and functions for FG nucleoporins in nucleocytoplasmic transport. Eukaryot Cell, 8(12), 1814-27, 2009.
- Beliakova-Bethell, N, Terry, LJ, Bilanchone, V, DaSilva, R, Nagashima, K, Wente, SR, Sandmeyer, S Ty3 nuclear entry is initiated by viruslike particle docking on GLFG nucleoporins. J Virol, 83(22), 11914-25, 2009.
- Carmody, SR, Wente, SR mRNA nuclear export at a glance. J Cell Sci, 122(Pt 12), 1933-7, 2009.
- Bolger, TA, Folkmann, AW, Tran, EJ, Wente, SR The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation. Cell, 134(4), 624-33, 2008.
- Sarmah, B, Winfrey, VP, Olson, GE, Appel, B, Wente, SR A role for the inositol kinase Ipk1 in ciliary beating and length maintenance. Proc Natl Acad Sci U S A, 104(50), 19843-8, 2007.
- Terry, LJ, Shows, EB, Wente, SR Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science, 318(5855), 1412-6, 2007.
- Alcazar-Roman, AR, Wente, SR Inositol polyphosphates: a new frontier for regulating gene expression. Chromosoma, 1171-13, 2007.
- Terry, LJ, Wente, SR Nuclear mRNA export requires specific FG nucleoporins for translocation through the nuclear pore complex. J Cell Biol, 178(7), 1121-32, 2007.
- Tran, EJ, Bolger, TA, Wente, SR SnapShot: nuclear transport. Cell, 131(2), 420, 2007.
- Tran, EJ, Zhou, Y, Corbett, AH, Wente, SR The DEAD-box protein Dbp5 controls mRNA export by triggering specific RNA:protein remodeling events. Mol Cell, 28(5), 850-9, 2007.
- Ryan, KJ, Zhou, Y, Wente, SR The karyopherin kap95 regulates nuclear pore complex assembly into intact nuclear envelopes in vivo. Mol Biol Cell, 18(3), 886-98, 2007.
- Tran, EJ, Wente, SR Dynamic nuclear pore complexes: life on the edge. Cell, 125(6), 1041-53, 2006.
- Alcazar-Roman, AR, Tran, EJ, Guo, S, Wente, SR Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nat Cell Biol, 8(7), 711-6, 2006.
- Miao, M, Ryan, KJ, Wente, SR The integral membrane protein Pom34p functionally links nucleoporin subcomplexes. Genetics, 172(3), 1441-57, 2006.
- Hoek, KL, Antony, P, Lowe, J, Shinners, N, Sarmah, B, Wente, SR, Wang, D, Gerstein, RM, Khan, WN Transitional B cell fate is associated with developmental stage-specific regulation of diacylglycerol and calcium signaling upon B cell receptor engagement. J Immunol, 177(8), 5405-13, 2006.
- Sarmah, B, Latimer, AJ, Appel, B, Wente, SR Inositol polyphosphates regulate zebrafish left-right asymmetry. Dev Cell, 9(1), 133-45, 2005.
- Kendirgi, F, Rexer, DJ, Alcazar-Roman, AR, Onishko, HM, Wente, SR Interaction between the shuttling mRNA export factor Gle1 and the nucleoporin hCG1: a conserved mechanism in the export of Hsp70 mRNA. Mol Biol Cell, 16(9), 4304-15, 2005.
- Miller, AL, Suntharalingam, M, Johnson, SL, Audhya, A, Emr, SD, Wente, SR Cytoplasmic inositol hexakisphosphate production is sufficient for mediating the Gle1-mRNA export pathway. J Biol Chem, 279(49), 51022-32, 2004.
- Strawn, LA, Shen, T, Shulga, N, Goldfarb, DS, Wente, SR Minimal nuclear pore complexes define FG repeat domains essential for transport. Nat Cell Biol, 6(3), 197-206, 2004.
- Suntharalingam, M, Alcazar-Roman, AR, Wente, SR Nuclear export of the yeast mRNA-binding protein Nab2 is linked to a direct interaction with Gfd1 and to Gle1 function. J Biol Chem, 27935384-91, 2004.
- Rayala, HJ, Kendirgi, F, Barry, DM, Majerus, PW, Wente, SR The mRNA Export Factor Human Gle1 Interacts with the Nuclear Pore Complex Protein Nup155. Mol Cell Proteomics, 3(2), 145-155, 2004.
- Kiseleva, E, Allen, T D, Rutherford, S, Bucci, M, Wente, SR, Goldberg, MW Yeast nuclear pore complexes have a cytoplasmic ring and internal filaments. J Struct Biol, 145(3), 272-88, 2004.
- Kendirgi, F, Barry, DM, Griffis, ER, Powers, MA, Wente, SR An essential role for hGle1 nucleocytoplasmic shuttling in mRNA export. J Cell Biol, 1601029-40, 2003.
- Suntharalingam, M, Wente, SR Peering through the Pore. Nuclear Pore Complex Structure, Assembly, and Function. Dev Cell, 4775-89, 2003.
- Steger, DJ, Haswell, ES, Miller, AL, Wente, SR, OShea, EK Regulation of chromatin remodeling by inositol polyphosphates. Science, 299114-6, 2003.
- Ryan, KJ, McCaffery, JM, Wente, SR The Ran GTPase cycle is required for yeast nuclear pore complex assembly. J Cell Biol, 1601041-53, 2003.
- Bayliss, R, Littlewood, T, Strawn, LA, Wente, SR, Stewart, M GLFG and FxFG nucleoporins bind to overlapping sites on importin-beta. J Biol Chem, 27750597-606, 2002.
- Ryan, KJ, Wente, SR Isolation and characterization of new Saccharomyces cerevisiae mutants perturbed in nuclear pore complex assembly. BMC Genet, 317, 2002.
- Sondermann, H, Ho, AK, Listenberger, LL, Siegers, K, Moarefi, I, Wente, SR, Hartl, FU, Young, JC Prediction of novel Bag-1 homologs based on structure/function analysis identifies Snl1p as an Hsp70 co-chaperone in S. cerevisiae. J. Biol. Chem., 277(36), 33220-7, 2002.
- Chang, S-C, Miller, AL, Feng, Y, Wente, SR, Majerus, PW The human homolog of the rat inositol phosphate multikinase is an inositol 1,3,4,6-tetrakisphosphate 5-kinase. J Biol Chem, 27743836-43, 2002.
- Verbsky, JW, Wilson, MP, Kisseleva, MV, Majerus, PW, Wente, SR The synthesis of inositol hexakisphosphate: Characterization of human inositol 1,3,4,5,6-pentakisphosphate 2-kinase. J. Biol. Chem., 277(35), 31857-62, 2002.
- Feng, Y, Wente, S R, Majerus, P W Overexpression of the inositol phosphatase SopB in human 293 cells stimulates cellular chloride influx and inhibits nuclear mRNA export. Proc Natl Acad Sci U S A, 98(3), 875-9, 2001.
- Carvalho, J, Bertram, P G, Wente, S R, Zheng, X F Phosphorylation regulates the interaction between Gln3p and the nuclear import factor Srp1p. J Biol Chem, 276(27), 25359-65, 2001.
- Strawn, L A, Shen, T, Wente, S R The GLFG regions of Nup116p and Nup100p serve as binding sites for both Kap95p and Mex67p at the nuclear pore complex. J Biol Chem, 276(9), 6445-52, 2001.
- Odom, A. R., Stahlberg, A., Wente, S. R., York, J. D A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control. Science, 2872026-2029, 2000.
- Ho, A K, Shen, T X, Ryan, K J, Kiseleva, E, Levy, M A, Allen, T D, Wente, S R Assembly and preferential localization of Nup116p on the cytoplasmic face of the nuclear pore complex by interaction with Nup82p. Mol Cell Biol, 20(15), 5736-48, 2000.
- Ives, EB, Nichols, J, Wente, SR, York, JD Biochemical and functional characterization of inositol 1,3,4,5, 6-pentakisphosphate 2-kinases. J. Biol. Chem., 27536575-83, 2000.
- Wente, S. R Gatekeepers of the nucleus. Science, 2881374-1377, 2000.
- Barry, D M, Wente, S R Nuclear transport: never-ending cycles of signals and receptors. Essays Biochem, 3689-103, 2000.
- Ryan, K and Wente, SR The nuclear pore complex: a protein machine bridging the nucleus and cytoplasm. Curr. Opin. Cell Biol., 12361-371, 2000.
- York, J. D., Odom, A. R., Murphy, R., Ives, E. B., Wente, S. R A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science, 28596-100, 1999.
- Bucci, M., Wente, S. R A novel fluorescence-based genetic strategy identifies mutants of Saccharomyces cerevisiae defective for nuclear pore complex assembly. Mol. Biol. Cell, 92439-2461, 1998.
- Watkins, J. L., Murphy, R., Emtage, J. L., Wente, S. R The human homologue of Saccharomyces cerevisiae Gle1p is required for poly(A)+ RNA export. Proc. Natl. Acad. Sci. USA, 956779-6784, 1998.
- Ho, A. K., Raczniak, G. A., Ives, E. B., Wente, S. R The integral membrane protein snl1p is genetically linked to yeast nuclear pore complex function. Mol. Biol. Cell, 9355-373, 1998.
- Iovine, M. K., Wente, S. R A nuclear export signal in Kap95p is required for both recycling the import factor and interaction with the nucleoporin GLFG repeat regions of Nup116p and Nup100p. J. Cell Biol., 137797-811, 1997.
- Emtage, J. L., Bucci, M., Watkins, J. L., Wente, S. R Defining the essential functional regions of the nucleoporin Nup145p. J. Cell Sci., 110911-925, 1997.
- Bucci, M., Wente, S. R In vivo dynamics of nuclear pore complexes in yeast. J. Cell Biol. , 1361185-1199, 1997.
- Murphy, R., Wente, S. R An RNA-export mediator with an essential nuclear export signal. Nature, 383357-360, 1996.
- Murphy, R., Watkins, J. L., Wente, S. R GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function. Mol. Biol. Cell, 71921-1937, 1996.
- Iovine, M. K., Watkins, J. L., Wente, S. R The GLFG repetitive region of the nucleoporin Nup116p interacts with Kap95p, an essential yeast nuclear import factor. J. Cell Biol. , 1311699-1713, 1995.
- Wente, S. R., Blobel, G NUP145 encodes a novel yeast glycine-leucine-phenylalanine-glycine (GLFG) nucleoporin required for nuclear envelope structure. J. Cell Biol., 125955-969, 1994.
- Rout, M P, Wente, S R Pores for thought: nuclear pore complex proteins. Trends Cell Biol, 4(10), 357-65, 1994.
- Wente, S. R., Blobel, G A temperature-sensitive NUP116 null mutant forms a nuclear envelope seal over the yeast nuclear pore complex thereby blocking nucleocytoplasmic traffic. J. Cell Biol. , 123275-284, 1993.
- Wente, S. R., Rout, M. P. , Blobel, G A new family of yeast nuclear pore complex proteins. J. Cell Biol. , 119705-723, 1992.
- Wente, S. R., Schachman, H. K Different amino acid substitutions at the same position in the nucleotide-binding site of aspartate transcarbamoylase have diverse effects on the allosteric properties of the enzyme. J. Biol. Chem., 26620833-20839, 1991.
- Wente, S. R., Rosen, O. M Insulin-receptor approaches to studying protein kinase domain. Diabetes Care, 13280-287, 1990.
- Wente, S. R., Villalba, R., Schrammm, V. L., Rosen, O. M Mn2(+)-binding properties of a recombinant protein-tyrosine kinase derived from the human insulin receptor. Proc. Natl. Acad. Sci. USA, 872805-2809, 1990.
- Villalba, M., Wente, S. R., Russell, D. S., Ahn, J. C., Reichelderfer, C. F., Rosen, O. M Another version of the human insulin receptor kinase domain: expression, purification, and characterization. Proc. Natl. Acad. Sci. USA, 867847-7852, 1989.
- Wente, S. R., Schachman, H. K Shared active sites in oligomeric enzymes: model studies with defective mutants of aspartate transcarbamoylase produced by site-directed mutagenesis. Proc. Natl. Acad. Sci. USA, 8431-35, 1987.
- Robey, E. A., Wente, S. R., Markby, D. W., Flint, A., Yang, Y. R., Schachman, H. K Effect of amino acid substitutions on the catalytic and regulatory properties of aspartate transcarbamoylase. Proc. Natl. Acad. Sci. USA, 835934-5938, 1986.