Nucleic Acids Research Advance Access originally published online on September 20, 2006
Nucleic Acids Research 2006 34(18):5007-5020; doi:10.1093/nar/gkl575
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Nucleic Acids Research, 2006, Vol. 34, No. 18 5007-5020
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
ZBP1 subcellular localization and association with stress granules is controlled by its Z-DNA binding domains
1 Institute for Immunology, University Hospital Eppendorf Hamburg, Germany 2 Department of Biology, Massachusetts Institute of Technology Cambridge, MA, USA
*To whom correspondence should be addressed. Tel: +49 40 428037922; Fax: +49 40 428034243; Email: rothenbu{at}uke.uni-hamburg.de
Received June 21, 2006. Revised July 24, 2006. Accepted July 25, 2006.
Z-DNA binding protein 1 (ZBP1) belongs to a family of proteins that contain the Z
domain, which binds specifically to left-handed Z-DNA and Z-RNA. Like all vertebrate proteins in the Z family, it contains two Z-like domains and is highly inducible by immunostimulation. Using circular dichroism spectroscopy and electrophoretic mobility shift assays we show that both Z domains can bind Z-DNA independently and that substrate binding is greatly enhanced when both domains are linked. Full length ZBP1 and a prominent splice variant lacking the first Z domain (
Z) showed strikingly different subcellular localizations. While the full length protein showed a finely punctate cytoplasmatic distribution, ZBP1Z accumulated in large cytoplasmic granules. Mutation of residues important for Z-DNA binding in the first Z domain resulted in a distribution comparable to that of ZBP1Z. The ZBP1Z granules are distinct from stress granules (SGs) and processing bodies but dynamically interacted with these. Polysome stabilization led to the disassembly of ZBP1Z granules, indicating that mRNA are integral components. Heat shock and arsenite exposure had opposing effects on ZBP1 isoforms: while ZBP1Z granules disassembled, full length ZBP1 accumulated in SGs. Our data link ZBP1 to mRNA sorting and metabolism and indicate distinct roles for ZBP1 isoforms.
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