Protein misfolding in human brain cells is the hallmark of neurodegenerative diseases, such as Alzheimer’s, Huntington’s disease or Amyotrophic Lateral Sclerosis (ALS). To identify new targets for therapies, scientists are trying to understand how cells protect themselves against the toxic formation and accumulation of misfolded proteins. RESOLV researcher Konstanze Winklhofer and colleagues from the RUB and the Max Planck Institute of Biochemistry of Martinsried near Munich have now shed light on a new quality control system of brain cells. The results have been published early online in the renowned EMBO Journal.
The scientists explored the protective role of a protein complex called linear ubiquitin chain assembly complex (LUBAC). LUBAC marks misfolded proteins with linear ubiquitin chains, stops them from interacting with other proteins in the cell and directs them towards disposal. The system works with various types of misfolded proteins linked to neurodegenerative diseases. “This is a highly specific process, because it’s mediated by a single LUBAC component. Thus, it may be exploited as a possible drug target”, says Winklhofer.
The protein complex LUBAC is known to be a regulator of innate immune signaling pathways, for example after infection of cells with bacteria and triggers an immune response mediated by the transcription factor NF-(kappa)B. “However, in our study LUBAC shows a novel function in protein quality control that is independent of the transcription factor NF-(kapp)B and applies to all kinds of misfolded proteins”, says Winklhofer. “It appears that LUBAC recognizes misfolded proteins as dangerous and marks them with linear ubiquitin chains", she adds. The RESOLV scientists found similar results for LUBAC with misfolded proteins involved in Huntington’s disease, ALS and frontotemporal dementia.
Original Publication: E. van Well, V. Bader et al.: A Protein quality control pathway regulated by linear ubiquitination, in:The EMBO Journal, 2019, DOI: 10.15252/embj.20181000730