Exploring function and dynamics in the human VCP/p97-cofactor network

• Applicant: Professor Dr. Hemmo Meyer
• Subject Area: Cell Biology
• Term: from 2013 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235789622

P97 (also called VCP or Cdc48) is a ubiquitin-directed AAA+-type ATPase with a large number of diverse cellular activities that range from stress response pathways and protein degradation to intracellular signalling. They are critical for genomic stability and protein homeostasis with relevance for degenerative disease and aging. To fulfil these functions, p97 is believed to associate with alternative sets of cofactor proteins and form pathway-specific p97-cofactor complexes. However, in most cases, these complexes are only poorly defined, while - conversely - a large number of predicted cofactors have not been assigned to functional complexes.In the previous funding period, we have successfully used stress-induced cofactor localisation screening combined with functional validation to define a novel cofactor complex in one p97-mediated process, the endo-lysosomal damage response. Our goal is to now further develop and apply the approach systematically in a range of cellular stress response pathways to functionally assign p97 cofactors and define distinct pathway-specific p97 complexes. The approach will be complemented with functional studies based on cellular knock-out and RNAi approaches using a range of established readouts, as well as with biochemical and microscopic analyses of cofactor complex assembly. This will help create a comprehensive picture of the p97-cofactor system, allow comparison of p97-mediated cellular stress responses and to study their relationship upon perturbations.The expected results will close a major gap in the understanding of what has emerged as a diverse and far-reaching stress response system, and will hopefully also reveal possible strategies for therapeutic intervention in p97-associated and related degenerative disorders.

• DFG Programme: Research Grants