Within each cell is a NUCLEUS, the ‘mothership’ of the human genome. Chromosomes are enclosed by the nuclear ‘envelope’: two membranes punctuated by Nuclear Pore Complexes and reinforced by a network of nuclear lamin filaments. The nuclear envelope and lamins create and maintain the special three-dimensional environment in which chromosomes are properly organized, expressed and replicated. The inner nuclear membrane, facing the chromosomes, is home to over 70 unique integral membrane proteins, many of which bind to lamins or chromosomes (or both). Mutations in a nuclear membrane protein named emerin cause X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD). Emerin protein is expressed throughout the body, but EDMD affects only three tissues, with contractures of major tendons, slowly progressive muscle wasting, and ventricular conduction defects that can cause sudden cardiac arrest (preventable by pacemaker/defibrillator). EDMD is also caused by autosomal dominant mutations in A-type lamins, which normally anchor emerin at the inner membrane.

Our goals are to understand the normal functions of emerin, why its loss causes EDMD, and how to compensate for these lost functions therapeutically. Research from our lab and others suggests emerin-deficient cells have defects in mechano-sensitive gene expression, nuclear architecture and signaling pathways that control tissue-specific gene expression. We therefore propose emerin functions as a ‘Signal Integrator’ at the nuclear envelope. This hypothesis is supported by a recent proteomic analysis of six distinct emerin-associated protein complexes purified from HeLa cell nuclei (Holaska & Wilson, 2007), and DNA microarray analysis of genes misregulated in emerin-deficient cells (Wilson lab, unpublished). We are now pursuing these high-throughput study results, and the roles of specific muscle-relevant binding partners for emerin including BAF (Barrier-to-Autointegration Factor), an essential histone-binding protein that is also exploited by, and essential for, Human Immunodeficiency Virus type 1 (HIV-1) to integrate into human chromosomes (Jacque & Stevenson, Nature, 2006). Thus, our BAF studies might yield insight into a crucial stage of HIV-1 infection, as well as BAF’s normal roles in muscle and other tissues. Collectively our work on BAF and emerin is aimed at discovering the molecular mechanism(s) of EDMD disease, but might also yield insight into the molecular basis of other ‘laminopathies’ including cardiomyopathy and progeria (accelerated aging) syndromes caused by mutations in A-type lamins.

Publications:

Holaska JM and Wilson KL (2007) An emerin ‘proteome’: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signaling, mechano-sensing and nuclear architecture. Biochemistry (in press)

Zastrow MS, Flaherty DB, Benian GM and Wilson KL (2006) Nuclear titin interacts with A- and B-type lamins in vitro and in vivo. J. Cell Science 119, 239-249.

Montes de Oca R, Lee KK and Wilson KL (2006) Binding of barrier-to-autointegration factor (BAF) to histone H3 and selected linker histones including H1.1. J. Biol. Chemistry 280, 42252-62.

Tifft K, Segura-Totten M, Lee KK and Wilson KL (2006) Barrier-to-autointegration factor- (BAF-) Like, a proposed regulator of BAF. Exp. Cell Res. 312, 478-487.

Bengtsson L and Wilson KL (2006) Barrier-to-autointegration factor phosphorylation on Ser-4 regulates emerin binding to lamin A in vitro and emerin localization in vivo. Mol. Biol. Cell 17, 1154-1163.

Wilson KL (2006) Integrity matters: linking nuclear architecture to lifespan. Proc Natl Acad Sci USA 102, 18767-8.

Dahl KN, Scaffidi P, Islam MF, Yodh AG, Wilson KL and Misteli T. (2006) Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford Progeria Syndrome. Proc Natl Acad Sci USA 103, 10271-10276.

Tzur YB, Wilson KL and Gruenbaum Y (2006) SUN-domain proteins: ‘Velcro’ that links the nucleoskeleton to the cytoskeleton. Nature Rev Mol. Cell Biol. 7, 782-788. epub PMID: 16926857.

Holaska JM and Wilson KL (2006) Multiple roles for emerin: Implications for Emery-Dreifuss muscular dystrophy. Anat. Rec A Discov Mol Cell Evol Biol. 288, 676-680.

Holaska JM, Rais-Bahrami S and Wilson KL (2006) Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes. Human Mol. Genet. 15, 3459-3472.

Margalit A, Segura-Totten M, Gruenbaum Y and Wilson KL (2005) Barrier-to-autointegration factor is required to stably segregate and enclose chromosomes within the nuclear envelope and assemble the nuclear lamina. Proc. Natl. Acad Sci USA 102, 3290-3295.

Wilson KL, Holaska JM, Montes de Oca RM, Tifft K, Zastrow M, Segura-Totten M, Mansharamani M, Bengtsson L (2005) Nuclear membrane protein emerin: roles in gene regulation, actin dynamics and human disease. Novartis Found Symp. 264, 51-58; discussion 58-62, 227-230.

Mansharamani M and Wilson KL (2005) Nuclear membrane protein MAN1: direct binding to emerin in vitro and two modes of binding to BAF. J. Biol. Chem. 280, 13863-70.

Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK and Wilson KL (2005) The nuclear lamina comes of age. Nature Reviews Molecular Cell Biology 6, 21-31.

Lee KK and Wilson KL (2004) All in the family: evidence for four new LEM-domain proteins Lem2 (NET-25), Lem3, Lem4 and Lem5 in the human genome. Symp Soc Exp Biol 56, 329-339.

Vlcek S, Foisner R and Wilson KL (2004) Lco1 is a novel widely-expressed lamin-binding protein in the nuclear interior. Exp. Cell Res. 298, 499-511.

Dahl KN, Kahn SM, Wilson KL and Discher DE (2004) The nuclear envelope lamina network has elasticity and a compressibility limit suggestive of a molecular shock absorber. J. Cell Science 117, 4779-4786.

Holaska, J.M., Kowalski, A.K., Wilson, K.L. (2004) Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLOS Biology 2(9):E231.

Haraguchi, T., Holaska, J.M., Yamame, M., Koujin, T., Wilson, K.L. and Hiraoka, Y. (2004) Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy. Eur J Biochem 271:1035-45.

Segura-Totten, M. and Wilson, K.L. (2004) BAF: roles in chromatin, nuclear structure and retrovirus integration. Trends Cell Biol 14:261-266.

Kiseleva, E., Drummond, S.P., Goldberg, M.W., Rutherford, S.A., Allen, T.D. and Wilson, K.L. (2004) Actin- and protein-4.1-containing filaments link nuclear pore complexes to subnuclear organelles in Xenopus oocyte nuclei. J Cell Sci 117:2481-90.

Shimi, T., Koujin, T., Segura-Totten, M., Wilson, K.L., Haraguchi, T., Hiraoka, Y. (2004) Dynamic interaction between BAF and emerin revealed by FRAP, FLIP, and FRET analyses in living HeLa cells. J Struct Biol 147:31-41.

Fridkin, A., Mills, E., Margalit, A., Neufeld, E., Lee, K.K., Feinstein, N., Cohen, M., Wilson, K.L., Gruenbaum, Y. (2004) Matefin, a Caenorhabditis elegans germ line-specific SUN-domain nuclear membrane protein, is essential for early embryonic and germ cell development. Proc Natl Acad Sci USA. 101:6987-92.

Bengtsson, L. and Wilson, K.L. (2004) Multiple and surprising new functions for emerin, a nuclear membrane protein. Curr Opin Cell Biol 16:73-79.

Zastrow, M.S., Vlcek, S. and Wilson, K.L. (2004) Proteins that bind A-type lamins: integrating isolated clues. J Cell Sci 117:979-87.

Mansharamani, M., Graham, D.R., Monie, D., Lee, K.K., Hildreth, J.E., Siliciano, R.F., Wilson, K.L. (2003) Barrier-to-autointegration factor BAF binds p55 Gag and matrix and is a host component of human immunodeficiency virus type 1 virions. J Virol 77:13084-92.

Cohen, M., Feinstein, N., Wilson, K.L. and Gruenbaum Y. (2003) Nuclear pore protein gp210 is essential for viability in HeLa cells and Caenorhabditis elegans. Mol Biol Cell 14:4230-7.

Wilkinson, F.L., Holaska, J.M., Zhang, Z., Sharma, A., Manilal, S., Holt, I., Stamm, S., Wilson, K.L. and Morris, G.E. (2003) Emerin interacts in vitro with the splicing-associated factor, YT521-B. Eur J Biochem 270:2459-66.

Holaska, J.M., Lee, K.K., Kowalski, A.K. and Wilson, K.L. (2003) Transcriptional repressor germ cell-less (GCL) and barrier-to-autointegration factor (BAF) compete for binding to emerin. J Biological Chemistry 278: 6969-6975.

Liu, J., Lee, K.K., Segura-Totten, M., Neufeld, E., Wilson, K.L. and Gruenbaum, Y. (2003) MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans. Proc Natl Acad Sci 100: 4598-603

Wolfner, M.F. and Wilson, K.L. (2001) The nuclear envelope: emerging roles in development and disease. Cell Molec Life Sci 58: 1737-1740.

Wilson, K.L. (2000) The nuclear envelope, muscular dystrophy, and gene expression. Trends Cell Biology 10: 125-129.

Lee, K.K., Gruenbaum, Y., Spann, P., Liu, J. and Wilson, K.L. (2000) C. elegans nuclear envelope proteins emerin, MAN1, lamin and nucleoporins reveal unique timing of nuclear envelope breakdown during mitosis. Mol Biol Cell 11: 3089-3099.