The role of linear ubiquitination in protein aggregation

• Applicant: Professorin Dr. Konstanze Winklhofer
• Subject Area: Cell Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 400967619

To maintain neuronal viability and homeostasis, neurons depend on efficient stress response and quality control pathways. Imbalances in these systems are associated with aging and various neurodegenerative diseases. Most if not all of these pathways are regulated by ubiquitination, such as proteasomal degradation, autophagy, and organellar stress response programs. Our preliminary results revealed that the linear ubiquitin assembly complex (LUBAC) is recruited to misfolded protein species associated with neurodegenerative diseases, such as mutant huntingtin with an elongated poly-glutamine tract. As a consequence, misfolded huntingtin is modified with linear polyubiquitin chains, resulting in a marked decrease of its neuronal toxicity. Based on these observations, we propose that cytoplasmic protein aggregates are sensed as a special kind of "cellular pathogens", resulting in the recruitment and activation of LUBAC with beneficial effects on neuronal proteostasis and viability. The aim of this proposal is to characterize the function of LUBAC in preventing proteotoxic stress and to elucidate the underlying mechanisms. We will combine imaging and biochemical approaches to experimentally address the following objectives:Objective 1: To analyze how linear ubiquitination influences Htt aggregate toxicityObjective 2: To address the impact of LUBAC on other aggregation-prone proteinsObjective 3: To explore a possible role of NEMO in maintaining proteostasis

• DFG Programme: Research Grants