Janitorial system in red blood cells discovered

Red blood cells are a stripped-down version of most other cells: The oxygen-carrying workhorses are packed with hemoglobin and little else. As immature red blood cells called reticulocytes transform into dedicated oxygen carriers, they trash their nucleus, organelles, and most proteins. Two groups of scientists are now reporting that this massive and selective clearance event occurs thanks to a protein degradation pathway involving an enzyme called UBE2O.

A team led by Daniel Finley and Mark D. Fleming at Harvard Medical School report that in the last stages of red blood cell differentiation, UBE2O remodels the proteome inside reticulocytes by tagging the small protein ubiquitin onto protein “trash” to signal for its breakdown, leaving the cell with approximately 98% α- and β-globin, the subunits that join to form hemoglobin (Science 2017, DOI: 10.1126/science.aan0218). Meanwhile, Ramanujan S. Hegde and his team at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, discovered that in reticulocytes, UBE2O also degrades rogue α-globin proteins that have not formed functional hemoglobin.

In other types of cells, Hegde’s team similarly found that UBE2O helps clear out orphan proteins that have also failed to join multiprotein complexes. The enzyme recognizes the proteins and tags them at many sites with individual ubiquitin molecules to signal for degradation.

This is unlike other ubiquitin-based degradation pathways, which tag proteins for destruction with long chains of ubiquitin molecules, explain Randolph Y. Hampton at the University of California, San Diego, and Catherine Dargemont at Paris Diderot University in an associated commentary (Science 2017, DOI: 10.1126/science.aao1896). “Further understanding of UBE2O and other quality-control pathways might open new therapeutic avenues” they add.