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Human Molecular Genetics Advance Access published online on November 10, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi003
© 2004 by Oxford University Press
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Article

The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B

Evan Reid 1*, James Connell 2, Thomas L. Edwards 3, Simon Duley 2, Stephanie E. Brown 2, and Christopher M. Sanderson 2

1 Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 2XY, United Kingdom
2 Medical Research Council Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge, CB10 1SB, UK
3 Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge CB2 2XY, UK

* To whom correspondence should be addressed.
Evan Reid, E-mail: ereid{at}hgmp.mrc.ac.uk


  Abstract

Pure hereditary spastic paraplegia is characterised by length-dependent degeneration of the distal ends of long axons. Mutations in spastin are the most common cause of the condition. We set out to investigate the function of spastin using a yeast two-hybrid approach to identify interacting proteins. Using full-length spastin as bait we identified as a binding partner CHMP1B, a protein associated with the ESCRT (endosomal sorting complex required for transport) -III complex. Several different approaches confirmed the physiological relevance of the interaction in mammalian cells. Epitope-tagged CHMP1B and spastin showed clear cytoplasmic co-localisation in Cos-7 and PC12 cells. CHMP1B and spastin interacted specifically in vitro and in vivo in {beta}-lactamase protein fragment complementation assays and spastin co-immunoprecipitated with CHMP1B. The interaction was mediated by a region of spastin lying between residues 80-196 and containing a microtubule interacting and trafficking domain. Expression of epitope-tagged CHMP1B in mammalian cells prevented the development of the abnormal microtubule phenotype associated with expression of ATPase-defective spastin. These data point to a role for spastin in intracellular membrane traffic events and provide further evidence to support the emerging recognition that defects in intracellular membrane traffic are a significant cause of motor neuron pathology.


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