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Molecular and Cellular Biology, May 2006, p. 3738-3751, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3738-3751.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

SUN1 Interacts with Nuclear Lamin A and Cytoplasmic Nesprins To Provide a Physical Connection between the Nuclear Lamina and the Cytoskeleton

Farhana Haque,1 David J. Lloyd,1,{dagger} Dawn T. Smallwood,1 Carolyn L. Dent,1 Catherine M. Shanahan,3 Andrew M. Fry,2 Richard C. Trembath,1 and Sue Shackleton1,2*

Department of Genetics,1 Department of Biochemistry, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom,2 Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom3

Received 30 June 2005/ Returned for modification 12 August 2005/ Accepted 24 February 2006

Nuclear migration and positioning within cells are critical for many developmental processes and are governed by the cytoskeletal network. Although mechanisms of nuclear-cytoskeletal attachment are unclear, growing evidence links a novel family of nuclear envelope (NE) proteins that share a conserved C-terminal SUN (Sad1/UNC-84 homology) domain. Analysis of Caenorhabditis elegans mutants has implicated UNC-84 in actin-mediated nuclear positioning by regulating NE anchoring of a giant actin-binding protein, ANC-1. Here, we report the identification of SUN1 as a lamin A-binding protein in a yeast two-hybrid screen. We demonstrate that SUN1 is an integral membrane protein located at the inner nuclear membrane. While the N-terminal domain of SUN1 is responsible for detergent-resistant association with the nuclear lamina and lamin A binding, lamin A/C expression is not required for SUN1 NE localization. Furthermore, SUN1 does not interact with type B lamins, suggesting that NE localization is ensured by binding to an additional nuclear component(s), most likely chromatin. Importantly, we find that the luminal C-terminal domain of SUN1 interacts with the mammalian ANC-1 homologs nesprins 1 and 2 via their conserved KASH domain. Our data provide evidence of a physical nuclear-cytoskeletal connection that is likely to be a key mechanism in nuclear-cytoplasmic communication and regulation of nuclear position.

* Corresponding author. Mailing address: Department of Biochemistry, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom. Phone: 44 116 229 7029. Fax: 44 116 229 7058. E-mail: ss115{at}le.ac.uk.

{dagger} Present address: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92122.

Molecular and Cellular Biology, May 2006, p. 3738-3751, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3738-3751.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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