Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control

作者：Yau Richard G; Doerner Kerstin; Castellanos Erick R; Haakonsen Diane L; Werner Achim; Wang Nan; Yang X William; Martinez Martin Nadia; Matsumoto Marissa L^*; Dixit Vishva M^*; Rape Michael^*

来源：Cell, 2017, 171(4): 918-+.

DOI：10.1016/j.cell.2017.09.040

Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood. Here, we engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their endogenous substrates. We show that K11/K48-linked chains are synthesized and processed by essential ubiquitin ligases and effectors that are mutated across neurodegenerative diseases; accordingly, these conjugates promote rapid proteasomal clearance of aggregation-prone proteins. By revealing key roles of K11/K48-linked chains in cell-cycle and quality control, we establish heterotypic ubiquitin conjugates as important carriers of biological information.

• 出版日期2017-11-2