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Human Molecular Genetics Advance Access originally published online on November 10, 2004
Human Molecular Genetics 2005 14(1):19-38; doi:10.1093/hmg/ddi003
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved

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

Evan Reid1,*,{dagger}, James Connell2,{dagger}, Thomas L. Edwards1, Simon Duley2, Stephanie E. Brown2 and Christopher M. Sanderson2

1Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge CB2 2XY, UK and 2Medical Research Council Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge CB10 1SB, UK

* To whom correspondence should be addressed at: Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, CB2 2XY, UK. Tel: +44 1223 762632; Fax: +44 1223 217054; Email: ereid{at}hgmp.mrc.ac.uk

Received August 6, 2004; Revised October 6, 2004; Accepted October 21, 2004

Pure hereditary spastic paraplegia is characterized 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 CHMP1B, a protein associated with the ESCRT (endosomal sorting complex required for transport)–III complex, as a binding partner. Several different approaches confirmed the physiological relevance of the interaction in mammalian cells. Epitope-tagged CHMP1B and spastin showed clear cytoplasmic co-localization in Cos-7 and PC12 cells. CHMP1B and spastin interacted specifically in vitro and in vivo in ß-lactamase protein fragment complementation assays, and spastin co-immunoprecipitated with CHMP1B. The interaction was mediated by a region of spastin lying between residues 80 and 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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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