Irradiation alters protein expression through direct effects on the 26S proteasome

5053

Irradiation slows protein degradation through the proteasome. Since these structures integrate with kinases and ubiquitination systems to control all cellular signaling and dictate the half-life of almost all cellular proteins, many of the cellular consequences of radiation exposure will be affected by this mechanism. Function of only the 26S proteasome, and not the immunoproteasome or the 20S constitutive proteasome is affected by radiation exposure, resulting in an increase in ubiquitinated proteins in irradiated cells. This, and other data, indicates that the radiation-sensitive target is in the19S cap and not in the enzymatically active core. 26S proteasome inhibition occurs over a wide radiation dose range, is maximal within minutes of exposure and recovers over 24hrs. All 3 enzymic activities (chymotrypsin-like, trypsin-like, and peptidylglutamyl-hydrolyzing) are affected. Recovery of function is, at least in part, by cells synthesizing de novo proteasome components. Remarkably, in vitro irradiation of semi-purified 26S proteasomes has the same inhibitory effect as whole cell irradiation and can be inhibited by free radical scavengers, indicating that the 26S proteasome is a novel redox-sensitive direct target of ionizing radiation. We have therefore shown that radiation-induced proteasome function is a physiological response that operates very rapidly to modulate intracellular signaling pathways and trigger stress responses to irradiation. The life span of many proteins is significantly and selectively altered and this mechanism will play a role in promoting the biological consequences of radiation exposure, such as cell cycle arrest, DNA repair, and apoptosis. The proteasome is therefore a novel target for therapeutic manipulation of radiation responses.