Journal Article

UBE2O remodels the proteome during terminal erythroid differentiation

Schmidt, Paul J., Fleming, Mark D., Tian, Geng, Shi, Yuan, Sendamarai, Anoop K., Kuehnle, Nathalie, Weiss, Mitchell J., Gygi, Steven P., Yao, Yu, Wilson-Grady, Joshua T., Kawan, Mona, Campagna, Dean R., Finley, Daniel, Paulo, Joao A., Prado, Miguel A., Min, Mingwei, Dederer, Verena, Justice, Monica J., Nguyen, Anthony T.

2017

Overview

The degradation of excess subunits of protein complexes is a major quality-control problem for the cell. How such “orphans” are recognized and tagged for degradation is poorly understood. Two papers identify a protein quality-control pathway that acts on some of the most abundant protein complexes in the human body: hemoglobin and ribosomes (see the Perspective by Hampton and Dargemont). Yanagitani et al. show that the central player in this process is an unusual enzyme (UBE2O) that recognizes substrates and tags them for destruction. Other quality-contr ol pathways tend to use separate factors for target selection (often a chaperone), ubiquitin donation (an E2), and ubiquitin conjugati on (an E3). Encoding all three activities in a single factor whose function can be reconstituted in a purified system provides a tractable route to detailed mechanistic and structural dissection. Nguyen et al. show the importance of the UBE2O pathway in the differentiation of red blood cells. Science , this issue p. 472 , p. eaan0218 ; see also p. 450 During terminal differentiation, a specialized state is achieved through the targeted elimination of preexisting proteins. During terminal differentiation, the global protein complement is remodeled, as epitomized by erythrocytes, whose cytosol is ~98% globin. The erythroid proteome undergoes a rapid transition at the reticulocyte stage; however, the mechanisms driving programmed elimination of preexisting cytosolic proteins are unclear. We found that a mutation in the murine Ube2o gene, which encodes a ubiquitin-conjugating enzyme induced during erythropoiesis, results in anemia. Proteomic analysis suggested that UBE2O is a broad-spectrum ubiquitinating enzyme that remodels the erythroid proteome. In particular, ribosome elimination, a hallmark of reticulocyte differentiation, was defective in Ube2o −/− mutants. UBE2O recognized ribosomal proteins and other substrates directly, targeting them to proteasomes for degradation. Thus, in reticulocytes, the induction of ubiquitinating factors may drive the transition from a complex to a simple proteome.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Amino acids / Anemia / Anemia - genetics / Anemia, Hypochromic - genetics / Animals / beta-Globins - genetics / beta-Globins - metabolism / Blood / Cytosol / Defects / Degradation / Differentiation / Dissection / Enzymes / Erythrocytes / Erythrocytes - cytology / Erythrocytes - enzymology / Erythroid cells / Erythroid Cells - cytology / Erythroid Cells - enzymology / Erythropoiesis / Erythropoiesis - genetics / Erythropoiesis - physiology / Free form / Genetic transformation / HEK293 Cells / Hemoglobin / Humans / Individualized Instruction / Logical Thinking / Lysates / Maturation / Mice / Mice, Inbred C57BL / Mice, Mutant Strains / Mitochondria / mRNA / Multiplexing / Mutants / Mutation / Organelles / Proteasome Endopeptidase Complex - metabolism / Proteasome inhibitors / Proteasomes / Protein turnover / Proteins / Proteome - metabolism / Proteomics / RESEARCH ARTICLE SUMMARY / Reticulocytes / Reticulocytes - cytology / Reticulocytes - enzymology / Ribosomal proteins / Ribosomal Proteins - metabolism / Ribosomes / Ribosomes - metabolism / Substrate inhibition / Substrates / Sucrose / Sugar / Ubiquitin / Ubiquitin-conjugating enzyme / Ubiquitin-Conjugating Enzymes - genetics / Ubiquitin-Conjugating Enzymes - metabolism / Ubiquitin-protein ligase / Ubiquitination