CHIP is a U-box-dependent E3 ubiquitin ligase -: Identification of Hsc70 as a target for ubiquitylation

被引:461
作者
Jiang, JH
Ballinger, CA
Wu, YX
Dai, Q
Cyr, DM
Höhfeld, J
Patterson, C
机构
[1] Univ N Carolina, Div Cardiol, Program Mol Cardiol, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA
[5] Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77550 USA
[6] Univ Texas, Med Branch, Sealy Ctr Mol Cardiol, Galveston, TX 77550 USA
[7] Univ Bonn, Inst Cell Biol, D-53121 Bonn, Germany
关键词
D O I
10.1074/jbc.M101968200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Proper folding of proteins (either newly synthesized or damaged in response to a stressful event) occurs in a highly regulated fashion. Cytosolic chaperones such as Hsc/Hsp70 are assisted by cofactors that modulate the folding machinery in a positive or negative manner. CHIP (carboxyl terminus of Hsc70-interacting protein) is such a cofactor that interacts with Hsc70 and, in general, attenuates its most well characterized functions. In addition, CHIP accelerates ubiquitin-dependent degradation of chaperone substrates. Using an in vitro ubiquitylation assay with recombinant proteins, we demonstrate that CHIP possesses intrinsic E3 ubiquitin ligase activity an promotes ubiquitylation. This activity is dependent on the carboxyl-terminal U-box. CHIP interacts functionally and physically with the stress-responsive ubiquitin-conjugating enzyme family UBCH5. Surprisingly, a major target of the ubiquitin ligase activity of CHIP is Hsc70 itself. CHIP ubiquitylates Hsc70, primarily with short, noncanonical multiubiquitin chains but has no appreciable effect on steady-state levels or half-life of this protein. This effect may have heretofore unanticipated consequences with regard to the chaperoning activities of Hsc70 or its ability to deliver substrates to the proteasome. These studies demonstrate that CHIP is a bona fide ubiquitin ligase and indicate that U-box-containing proteins may comprise a new family of E3s.
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页码:42938 / 42944
页数:7
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