Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins

Nadinath B. Nillegoda, Maria A. Theodoraki, Atin K. Mandal, Katie J. Mayo, Hong Yu Ren, Rasheda Sultana, Kenneth Wu, Jill Johnson, Douglas M. Cyr, Avrom J. Caplan

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93 Citations (Scopus)

Abstract

Quality control systems facilitate polypeptide folding and degradation to maintain protein homeostasis. Molecular chaperones promote folding, whereas the ubiquitin/proteasome system mediates degradation. We show here that Saccharomyces cerevisiae Ubr1 and Ubr2 ubiquitin ligases promote degradation of unfolded or misfolded cytosolic polypeptides. Ubr1 also catalyzes ubiquitinylation of denatured but not native luciferase in a purified system. This activity is based on the direct interaction of denatured luciferase with Ubr1, although Hsp70 stimulates polyubiquitinylation of the denatured substrate. We also report that loss of Ubr1 and Ubr2 function suppressed the growth arrest phenotype resulting from chaperone mutation. This correlates with increased protein kinase maturation and indicates partitioning of foldable conformers toward the proteasome. Our findings, based on the efficiency of this quality control system, suggest that the cell trades growth potential to avert the potential toxicity associated with accumulation of unfolded or misfolded proteins. Ubr1 and Ubr2 therefore represent E3 components of a novel quality control pathway for proteins synthesized on cytosolic ribosomes.

Original languageEnglish
Pages (from-to)2102-2116
Number of pages15
JournalMolecular Biology of the Cell
Volume21
Issue number13
DOIs
Publication statusPublished - 1 Jul 2010
Externally publishedYes

Cite this

Nillegoda, N. B., Theodoraki, M. A., Mandal, A. K., Mayo, K. J., Ren, H. Y., Sultana, R., Wu, K., Johnson, J., Cyr, D. M., & Caplan, A. J. (2010). Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins. Molecular Biology of the Cell, 21(13), 2102-2116. https://doi.org/10.1091/mbc.E10-02-0098