Multiubiquitylation Pathways Involved in Muscle Assembly
Final Report Abstract
We revealed a novel functional interaction between UFD-2, the Caenorhabditis elegans ortholog of yeast UFD2, and CHN-1, a homolog of the human cochaperone CHIP. In fact, UFD-2 and CHN-1 form a complex that apparently increases polyubiquitylation and turnover of UNC-45, which determines myosin folding and assembly during muscle development. Conceptually, these findings support a novel mechanism in which two E3 enzymes, UFD-2 and CHN-1, team up to achieve polyubiquitin chain formation. The assembly of such an E3 complex in multicellular organisms could be controlled by tissue specific co-expression of both E3 enzymes in a developmentally-regulated manner. Furthermore, different combinations of E3 enzymes might provide a general principle to control the specificity and architecture of substrate ubiquitylation. Indeed, we identified that beside its role in myosin assembly, CHN-1 alternatively cooperates with another E3 enzyme throughout substrate ubiquitylation, the C. elegans Parkin homolog PDR-1. Our work discovered an unanticipated role of the ubiquitin-selective chaperone CDC-48/p97 in myosin assembly and myofibril organization both in C. elegans and humans. The developmentally regulated assembly of a CDC-48/UFD-2/CHN-1 complex links turnover of the myosin chaperone UNC-45 to functional muscle formation. Our data suggest a similarly conserved pathway regulating myosin assembly in man. Remarkably, mutations in human p97, known to cause hereditary inclusion body myopathy, abrogate this muscle-specific activity and result in severely disorganized myofibrils. These results identify a key role of CDC-48/p97 in the process of myofiber differentiation and maintenance, which is abolished during pathological conditions leading to protein aggregation and inclusion body formation in human skeletal muscle. How mutations in p97 establish protein aggregates and finally inclusion bodies is not understood at present. Therefore, our future studies will investigate the relationship between ubiquitin-dependent degradation of misfolded proteins, inclusion body formation and age-related diseases. This work was honored with the Werner Otto Research Award in 2007 and the Felix-Jerusalem Award of the German Society for Muscular Diseases (DGM) in 2008 given to Thorsten Hoppe, and with the Gebhard Koch Prize in cellular biochemistry for the Doctoral thesis of Johnny Kim in 2009.
Publications
- (2006). The ubiquitin/proteasome system and muscle development. Protein Degradation 3, Wiley-VCH, 21-39
Kim J., and Hoppe T.
(See online at https://doi.org/10.1002/9783527620227.ch2) - (2007). The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy. Nat. Cell Biol. 9, 379-90
Janiesch P.C., Kim J., Mouysset J., Barikbin R., Lochmüller H., Cassata G., Krause S., and Hoppe T.
(See online at https://doi.org/10.1038/ncb1554) - (2007). The UNC-45 Chaperone Mediates Sarcomere Assembly through Myosin Degradation in C. elegans. J. Cell Biol. 177, 205-10
Landsverk M.L., Hutagalung A.H., Li S., Najafov A., Hoppe T., Barral J.M., and Epstein H.F.
(See online at https://doi.org/10.1083/jcb.200607084) - (2008). Protein quality control gets muscle into shape. Trends Cell Biol. 18, 264-72
Kim J., Löwe T., and Hoppe T.
(See online at https://doi.org/10.1016/j.tcb.2008.03.007) - (2009). Less is more: how protein degradation regulates muscle development. Ernst Schering Found Symp Proc. 1, 67-73
Hoppe T.
(See online at https://doi.org/10.1007/2789_2008_101)
