Marques Carla, Guo Weimin, Pereira Paulo, Taylor Allen, Patterson Cam, Evans Paul C, Shang Fu
Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.
FASEB J. 2006 Apr;20(6):741-3. doi: 10.1096/fj.05-5080fje. Epub 2006 Feb 9.
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.
受损蛋白质的积累与许多年龄相关疾病存在因果关系。泛素-蛋白酶体途径（UPP）在受损蛋白质的选择性降解中发挥作用，而分子伴侣，如热休克蛋白，则参与变性蛋白质的重折叠。这项工作首次证明UPP和分子伴侣以竞争方式发挥作用，并且变性蛋白质的命运由UPP和分子伴侣的相对活性决定。增强的UPP活性会抑制变性蛋白质的重折叠，而升高的伴侣活性会抑制变性蛋白质的降解。CHIP是一种具有E3活性的共伴侣，在决定受损蛋白质的命运中起关键作用。UPP介导的变性蛋白质降解和重折叠之间的微妙平衡由CHIP和其他分子伴侣的相对水平控制。异肽酶是逆转CHIP作用的酶，在决定变性蛋白质的命运中也起重要作用。
