Protein Quality Control Relay

Cover for Molecular Cell
3 July, 2014
Volume 55, Issue 1

View the cover and the story 
on Molecular Cell website

MolCell-Lili

During her Ph.D. research, Lili explored the connection between cancer signaling pathway and protein quality control system for neurodegenerative diseases. Protein is essential for all forms of lives. All proteins need to be folded into a correct structure to become functional. Proteins that fail to form correct structure, namely misfolded proteins, are not only dysfunctional, but also toxic to cells. Misfolded protein are the underlying cause to many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and spinocerebellar ataxias (SCA). Healthy cells have defensive mechanisms to remove aberrant proteins. However, these mechanisms are poorly understood. It is also unclear why some misfolded proteins can escape the system and cause diseases. For this project, Lili identified a novel cellular protein quality control mechanism that recognizes and removes many types of toxic misfolded proteins. The key players in this system are promyelocytic protein (PML), a protein identified initially in promyelocytic leukemia, and another protein, RNF4. Lili showed that PML protein has a special region that can recognize and bind to misfolded proteins. Lili demonstrated the activity of PML to label misfolded proteins with a small protein tag called SUMO (small ubiquitin-like modifier). SUMO modified misfolded proteins are handed off to RNF4, which places a second tag called ubiquitin to the misfolded proteins. Ubiquitin is a signal recognized by a protein degradation machinery, proteasome. As a result of the tagging relay, the misfolded proteins are degraded by proteasome. Using cell culture models, Lili have showed that this system can effectively remove pathogenic proteins that cause amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and spinocerebellar ataxias (SCA). This work was published on Molecular Cell, 2014.

 

Cover image: Cellular protein quality control system comprised of PML (pink) and RNF4 (purple) proteins. This system selects misfolded proteins (deformed boxes), tag them with degradation signals (red and white labels), and send them for destruction by proteasome (green). The red tag represents SUMO and the white tag represents ubiquitin.



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