Redox modulation of cellular metabolism through targeted degradation of signaling proteins by the proteasome.
Under conditions of oxidative stress, the 20S proteasome plays a critical role in maintaining cellular homeostasis through the selective degradation of oxidized and damaged proteins. This adaptive stress response is distinct from ubiquitin-dependent pathways in that oxidized proteins are recognized and degraded in an ATP-independent mechanism, which can involve the molecular chaperone Hsp90. Like the regulatory complexes 19S and 11S REG, Hsp90 tightly associates with the 20S proteasome to mediate the recognition of aberrant proteins for degradation. In the case of the calcium signaling protein calmodulin, proteasomal degradation results from the oxidation of a single surface exposed methionine (i.e., Met145); oxidation of the other eight methionines has a minimal effect on the recognition and degradation of calmodulin by the proteasome. Since cellular concentrations of calmodulin are limiting, the targeted degradation of this critical signaling protein under conditions of oxidative stress will result in the downregulation of cellular metabolism, serving as a feedback regulation to diminish the generation of reactive oxygen species. The targeted degradation of critical signaling proteins, such as calmodulin, can function as sensors of oxidative stress to downregulate global rates of metabolism and enhance cellular survival.
Cell Biology and Biochemistry Group, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA. thomas.squier@pnl.gov
Thomas C
TC
Squier
D000818:Animals; D002147:Calmodulin / Q000378:metabolism; D002468:Cell Physiological Phenomena; D002477:Cells / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D008715:Methionine / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000502:physiology*
D002147:Calmodulin; D006360:Heat-Shock Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D008715:Methionine; D046988:Proteasome Endopeptidase Complex