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J. Biol. Chem., Vol. 276, Issue 46, 42938-42944, November 16, 2001
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From the 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 and 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.
CHIP Is a U-box-dependent E3 Ubiquitin Ligase
IDENTIFICATION OF Hsc70 AS A TARGET FOR UBIQUITYLATION*
§,,
,, and**§§
Program in Molecular Cardiology and
Lineberger Comprehensive Cancer Center, the Department of
Pharmacology, and the ** Department of Cell and Developmental
Biology, University of North Carolina, Chapel Hill, North Carolina
27599-7075, the § Department of Pharmacology and Toxicology
and ¶ Sealy Center for Molecular Cardiology, University of Texas
Medical Branch, Galveston, Texas 27599, and the
Institute for Cell Biology, University
of Bonn, Bonn, Germany D-53121
*
These studies were supported by National Institutes of
Health Grants HL03658, GM61728, and HL65619 (to C. P.) and GM56981 (to
D. M. C.); grants from the Cystic Fibrosis Foundation (to D. M. C.); and Deutsche Forschungsgemeinschaft Grant Ho1518/5-1 (to
J. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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J. Jiang, D. Cy |
