Researchers have identified a protein complex that marks misfolded proteins, stops them from interacting with other proteins in the cell and directs them towards disposal. An interdisciplinary team has identified the so-called Linear Ubiquitin Chain Assembly Complex, Lubac for short, as a crucial player in controlling misfolded proteins in cells.
The group is hoping to find a new therapeutic approach to treat neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's chorea, all of which are associated with misfolded proteins. The team published its report in "The Embo Journal".
Earlier studies have revealed that the protein complex Lubac regulates signalling pathways of the innate immune response that are mediated by the transcription factor NF-kB. For example, Lubac can be recruited to trigger immune responses by binding to bacteria in the cells and activating NF-kB.
"Our study revealed that the Lubac system has a previously unknown function," says the senior author. "It appears that Lubac recognises misfolded proteins as dangerous and marks them with linear ubiquitin chains, thus rendering them harmless to nerve cells." Unlike its response to bacteria, this function of Lubac is independent of the transcription factor NF-kB.
Aggregates of misfolded proteins are toxic to cells, because they interfere with various processes. For example, they expose an interactive surface thereby sequestering and inactivating other proteins that are essential for the cell. This process disrupts the function of nerve cells and can cause cell death.
The research team has now decoded the mechanism described above using the huntingtin protein, the misfolding of which causes Huntington's disease. HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP‐dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain‐containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease.
In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect.
The protective effect of Lubac is not limited to huntingtin aggregates. The researchers also detected linear ubiquitin chains attached to protein aggregates that play a role in other neurodegenerative disorders, for example in amyotrophic lateral sclerosis.
"The attachment of linear ubiquitin chains is a highly specific process, as there is only one protein - namely a Lubac-component - that can mediate it," explains the senior author. "Based on these insights, strategies for new therapeutic approaches could be developed."
In future studies, the team intends to identify small molecules that affect linear ubiquitination and to test if they have any positive effects on neurodegeneration. "But there is still a long way ahead until a drug can be developed," concludes the senior author.
How nerve cells mark the misfolded proteins for degradation
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