Heat shock and oxygen radicals stimulate ubiquitin-dependent degradation mainly of newly synthesized proteins.
Accumulation of misfolded oxidant-damaged proteins is characteristic of many diseases and aging. To understand how cells handle postsynthetically damaged proteins, we studied in Saccharomyces cerevisiae the effects on overall protein degradation of shifting from 30 to 38 degrees C, exposure to reactive oxygen species generators (paraquat or cadmium), or lack of superoxide dismutases. Degradation rates of long-lived proteins (i.e., most cell proteins) were not affected by these insults, even when there was widespread oxidative damage to proteins. However, exposure to 38 degrees C, paraquat, cadmium, or deletion of SOD1 enhanced two- to threefold the degradation of newly synthesized proteins. By 1 h after synthesis, their degradation was not affected by these treatments. Degradation of these damaged cytosolic proteins requires the ubiquitin-proteasome pathway, including the E2s UBC4/UBC5, proteasomal subunit RPN10, and the CDC48-UfD1-NPL4 complex. In yeast lacking these components, the nondegraded polypeptides accumulate as aggregates. Thus, many cytosolic proteins proceed through a prolonged "fragile period" during which they are sensitive to degradation induced by superoxide radicals or increased temperatures.
Medicherla
Balasubrahmanyam
B
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Goldberg
Alfred L
AL
D002104:Cadmium / Q000494:pharmacology; D018869:Heat-Shock Response / Q000187:drug effects*; D009154:Mutation / Q000235:genetics; D016877:Oxidants / Q000494:pharmacology; D010269:Paraquat / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*
D016877:Oxidants; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; D002104:Cadmium; D013482:Superoxide Dismutase; D046988:Proteasome Endopeptidase Complex; D010269:Paraquat