The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones.
Accumulation of damaged proteins is causally related to many age-related diseases. The ubiquitin-proteasome pathway (UPP) plays a role in selective degradation of damaged proteins, whereas molecular chaperones, such as heat shock proteins, are involved in refolding denatured proteins. This work demonstrates for the first time that the UPP and molecular chaperones work in a competitive manner and that the fates of denatured proteins are determined by the relative activities of the UPP and molecular chaperones. Enhanced UPP activity suppresses the refolding of denatured proteins whereas elevated chaperone activity inhibits the degradation of denatured proteins. CHIP, a co-chaperone with E3 activity, plays a pivotal role in determining the fates of the damaged proteins. The delicate balance between UPP-mediated degradation and refolding of denatured proteins is governed by relative levels of CHIP and other molecular chaperones. Isopeptidases, the enzymes that reverse the actions of CHIP, also play an important role in determining the fate of denatured proteins.
Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.
Carla
C
Marques
Weimin
W
Guo
Paulo
P
Pereira
Allen
A
Taylor
Cam
C
Patterson
Paul C
PC
Evans
Fu
F
Shang
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015971:Gene Expression Regulation, Enzymologic; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D008156:Luciferases / Q000737:chemistry / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011489:Protein Denaturation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D025801:Ubiquitin; D008156:Luciferases; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex