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

  • Cell. 2017 Nov 2;171(4):918-933.e20. doi: 10.1016/j.cell.2017.09.040.
Richard G Yau  1 ,  Kerstin Doerner  2 ,  Erick R Castellanos  3 ,  Diane L Haakonsen  1 ,  Achim Werner  2 ,  Nan Wang  4 ,  X William Yang  4 ,  Nadia Martinez-Martin  5 ,  Marissa L Matsumoto  6 ,  Vishva M Dixit  7 ,  Michael Rape  8
Affiliations
  • 1. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA; Howard Hughes Medical Institute, Berkeley, CA, USA.
  • 2. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA.
  • 3. Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA.
  • 4. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA.
  • 5. Department of Microchemistry, Proteomics, and Lipidomics, Genentech Inc., South San Francisco, CA, USA.
  • 6. Department of Structural Biology, Genentech Inc., South San Francisco, CA, USA. Electronic address: [email protected].
  • 7. Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA, USA. Electronic address: [email protected].
  • 8. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA; Howard Hughes Medical Institute, Berkeley, CA, USA. Electronic address: [email protected].
PMID: 29033132 DOI: 10.1016/j.cell.2017.09.040
Abstract

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.

Keywords
Huntingtin; Huntington’s disease; anaphase-promoting complex; branched ubiquitin chain; proteasome; protein quality control; ubiquitin; ubiquitin chain.