USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway
Abstract
Protein homeostasis is fundamental to the functioning of all living cells. Perturbation of the homeostasis, or proteotoxicity, plays an important role in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative diseases. To guard against proteotoxicity, cells have evolved sophisticated quality-control mechanisms that make adaptations including enhanced turnover of misfolded proteins. However, how the quality-control systems are coordinated through higher-order regulatory pathways is not fully understood. We have discovered a unique suppressor of proteotoxicity, the ubiquitin-specific protease USP7, whose action is conserved from invertebrate to mammalian systems and mediated by a substrate cascade involving NEDD4L and SMAD2. These findings reveal a previously unknown regulatory pathway for protein quality control and provide new strategies for developing interventions for neurodegenerative diseases.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 26, 2020
- Source ID
- 10.1073/pnas.2014349117
Entities
People
- Goran Periz
- Jiou Wang
- Tao Zhang
- Yu-Ning Lu
Organizations
- ALS Association
- Johns Hopkins University
- Muscular Dystrophy Association
- National Institutes of Health
- United States Department of Defense