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Interactome network analysis identifies multiple caspase-6 interactors involved in the pathogenesis of HD

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Item Type:Article
Title:Interactome network analysis identifies multiple caspase-6 interactors involved in the pathogenesis of HD
Creators Name:Riechers, S.P. and Butland, S. and Deng, Y. and Skotte, N. and Ehrnhoefer, D.E. and Russ, J. and Laine, J. and Laroche, M. and Pouladi, M.A. and Wanker, E.E. and Hayden, M.R. and Graham, R.K.
Abstract:Caspase-6 (CASP6) has emerged as an important player in Huntington disease (HD), Alzheimer disease (AD) and cerebral ischemia, where it is activated early in the disease process. CASP6 also plays a key role in axonal degeneration, further underscoring the importance of this protease in neurodegenerative pathways. As a protein's function is modulated by its protein-protein interactions we performed a high throughput yeast-2-hybrid (Y2H) screen against ∼17,000 human proteins to gain further insight into the function of CASP6. We identified a high confidence list of 87 potential CASP6 interactors. From this list, 61% are predicted to contain a CASP6 recognition site. Of nine candidate substrates assessed, six are cleaved by CASP6. Proteins that did not contain a predicted CASP6 recognition site were assessed using a LUMIER assay approach and 51% were further validated as interactors by this method. Of note, 54% of the high-confidence interactors identified show alterations in human HD brain at the mRNA level, and there is a significant enrichment for previously validated huntingtin (HTT) interactors. One protein of interest, STK3, a proapoptotic kinase, was validated biochemically to be a CASP6 substrate. Furthermore, our results demonstrate that in striatal cells expressing mutant huntingtin (mHTT) an increase in full length and fragment levels of STK3 are observed. We further show that caspase-3 is not essential for the endogenous cleavage of STK3. Characterization of the interaction network provides important new information regarding key pathways of interactors of CASP6 and highlights potential novel therapeutic targets for HD, AD and cerebral ischemia.
Keywords:Binding Sites, Biological Models, Caspase 6, Cell Line, Gene Expression Regulation, Huntingtin Protein, Huntington Disease, Post-Translational Protein Processing, Protein Interaction Maps, Protein-Serine-Threonine Kinases, Two-Hybrid System Techniques
Source:Human Molecular Genetics
Publisher:Oxford University Press
Page Range:1600-1618
Date:May 2016
Official Publication:https://doi.org/10.1093/hmg/ddw036
PubMed:View item in PubMed

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