ReviewCHIP: a quality-control E3 ligase collaborating with molecular chaperones
Introduction
Over 30% of newly-synthesized cellular proteins are discarded without being properly folded (Schubert et al., 2000). Even when proteins are normally formed into tertiary structures, the high density of protein molecules in the cytosol increases the spontaneous denaturation and consequently the likelihood of partially folded or unfolded proteins to undergo off-pathway reactions, such as aggregation. In addition, environmental stresses such as heat, oxidation (i.e. formation of free radicals), and ultraviolet, could result in the production of impaired proteins. However, those proteins with non-native or aberrant structures are rapidly removed inside the cells. In this regard, the cellular apparatus monitoring the “normality” of proteins in the cell is usually referred to as “the protein quality control system” (Wickner, Maurizi, & Gottesman, 1999). This monitoring machinery is considered an integral cellular component involved in maintaining cell survival and homeostasis, because it prevents the accumulation of abnormal proteins, formation of toxic inclusion bodies, followed by cell death, as seen in various neurodegenerative diseases. Indeed, there are growing lines of evidence of the potential link between failure of the protein quality control and neurodegeneration (Sherman & Goldberg, 2001). Hence, it is important to characterize the quality control mechanism of the cell for our understanding of the molecular basis underlying neurodegenerative diseases.
Section snippets
Chaperones and ubiquitin–proteasome system in protein quality control
Most cellular proteins in eukaryotic cells are targeted for degradation by the 26S proteasome, a eukaryotic ATP-dependent protease, usually after they have been covalently attached ubiquitin in the form of a polyubiquitin chain with linkages involving lysine 48 (K48-linked polyubiquitin chain) functioning as a degradation signal (Glickman & Ciechanover, 2002). This ubiquitylation reaction is catalyzed by a cascade system, consisting of activating (E1), conjugating (E2), and ligating (E3)
TPR motif and U-box domain of CHIP
Recently, a 35-kDa protein called carboxyl-terminus of Hsc70 interacting protein (CHIP) was identified as a candidate for a ubiquitin ligase that plays a role in the protein quality control. First, CHIP was identified during screening a library with a cDNA fragment coding tetratricopeptide repeat (TPR) motifs (Ballinger et al., 1999) (Fig. 1). Subsequent studies revealed that CHIP possessed two characteristic domains; one is the TPR domain at its amino terminus, which serves as the
CHIP is a chaperone-dependent ubiquitin ligase
Subsequent studies revealed that this is true. In cells transfected with CHIP and glucocorticoid receptor (GR), a well-known substrate of Hsp90 for its maturation, CHIP promoted dissociation of p23, a co-chaperone of Hsp90, from Hsp90, and at the same time ubiquitylated GR (Connell et al., 2001). While dissociation of p23 was U-box-independent, the ubiquitylating activity was U-box-dependent, indicating the two characteristic domains of CHIP attenuate GR mediated signaling separately but
Interaction between molecular chaperones and CHIP
How does CHIP discriminate between what is to be degraded and what will be properly folded? For CHIP to ubiquitylate its target proteins, it is required that targets are first captured by molecular chaperones. However, the substrates of Hsp90 and those of Hsc/Hsp70 are presented to CHIP in a quite different way. It is shown that CHIP and p23 compete for binding to Hsp90, although the binding sites of these in Hsp90 are different, that is, the former binds to the C-terminus while the latter
Substrates of CHIP
What are the natural substrates of CHIP in vivo? The present understating is based on the results of studies employing either cells that overexpress CHIP cDNA or in vitro reconstitution system. However, the levels of Hsc70 are about 6 times greater than those of Hdj-2, which are about 10 times greater than those of CHIP in HEK293 cells (Meacham et al., 2001). Therefore, one cannot conclude that GR and CFTR are the natural substrates of CHIP since overexpression of CHIP could ubiquitylate these
Possible role of CHIP in neurodegenerative diseases
Although CHIP is expected to play a general role in the protein quality control, its expression level varies in various mouse tissues. The mRNA levels of CHIP are high in the skeletal muscles, heart, pancreas, and the brain (Ballinger et al., 1999). However, the protein of CHIP is highly expressed in the brain (Murata et al., unpublished data). Since neurons do not regenerate themselves, it is conceivable that the protein quality control system is more important in the brain than in other
Concluding remarks
The recent studies have revealed that CHIP is a ubiquitin ligase that ubiquitylates and promote degradation of unfolded and misfolded proteins in a chaperone-assisted manner. However, there are still major unanswered questions about CHIP. One question is “how does CHIP change folding machinery to degradation machinery?” Does it require another trigger factor? Is upregulation of CHIP sufficient for the switching, as shown by overexpression experiments? Alternatively, only hopelessly misfolded
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