ABSTRACT
Selective breakdown of proteins and aggregates is crucial for maintaining normal cellular activities and is involved in the pathogenesis of diverse diseases. How the cell recognizes and tags these targets in different structural states for degradation by the proteasome and autophagy pathways has not been well understood. Here, we discovered that a HECT-family ubiquitin ligase HUWE1 is broadly required for the efficient degradation of soluble factors and for the clearance of protein aggregates/condensates. Underlying this capacity of HUWE1 is a novel Ubiquitin-Directed ubiquitin Ligase (UDL) activity which recognizes both soluble substrates and aggregates that carry a high density of ubiquitin chains and rapidly expand the ubiquitin modifications on these targets. Ubiquitin signal amplification by HUWE1 recruits the ubiquitin-dependent segregase p97/VCP to process these targets for subsequent degradation or clearance. HUWE1 controls the cytotoxicity of protein aggregates, mediates Targeted Protein Degradation and regulates cell-cycle transitions with its UDL activity.
Competing Interest Statement
E.S.F. is a founder, member of the scientific advisory board (SAB), and equity holder of Civetta Therapeutics, Proximity Therapeutics, and Neomorph Inc (also board of directors), SAB member and equity holder in Avilar Therapeutics and Photys Therapeutics, equity holder in Lighthorse Therapeutics, and a consultant to Astellas, Sanofi, Novartis, Deerfield, EcoR1 capital, Odyssey Therapeutics and Ajax Therapeutics. The Fischer laboratory receives or has received research funding from Novartis, Deerfield, Ajax, Interline, and Astellas. K.A.D is a consultant to Kronos Bio and Neomorph Inc. Y. L. is a member of the SAB of Momentum Biotechnologies, and is a consultant to Care Equity Capital Management.