Cell Biology

A Less Toxic Treatment

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Science  01 Apr 2011:
Vol. 332, Issue 6025, pp. 14-15
DOI: 10.1126/science.332.6025.14-d

Cells frequently tag proteins that are targeted for destruction by the proteasome with ubiquitin, a process that is important for maintaining cellular homeostasis and health. Besides defunct or aberrant cytosolic proteins, misfolded endoplasmic reticulum–derived proteins are “dislocated” back into the cytosol, ubiquitinated, and degraded by the proteasome. Proteasome inhibitors that block various stages of these processes exist and are useful for studying this biological process, but are often quite toxic. Ernst et al. describe an alternative approach to interfere with the ubiquitin proteasome (UPS) pathway. A highly active ubiquitin-specific protease domain was used to remove ubiquitin preemptively from substrates about to be destroyed, and so stabilize them. The technique allowed the uncoupling of dislocation and degradation of endoplasmic reticulum–derived misfolded proteins. This approach efficiently and globally blocked the UPS pathway, but was less cytotoxic than commonly used pharmacological inhibitors.

PLOS Biol. 8, e1000605 (2011).

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