CHIP Is Associated with Parkin, a Gene Responsible for Familial Parkinson's Disease, and Enhances Its Ubiquitin Ligase Activity

Imai, Yuzuru; Soda, Mitsuhiro; Hatakeyama, Susumi; Akagi, Tomonori; Hashikawa, Tsutomu; Nakayama, Kei Ichi; Takahashi, Ryōsuke

doi:10.1016/s1097-2765(02)00583-x

Cited by 451 publications

(383 citation statements)

References 32 publications

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“…Nonetheless, we cannot completely rule out that a given cellular context or a cofactor not present in our assay might tilt the balance toward PICK1 polyubiquitination under certain circumstances. For instance, the E4 activity mediated by CHIP (carboxy-terminus of the Hsp70-interacting protein) has been previously shown to enhance polyubiquitin chain formation on the parkin substrate Pael-R (Imai et al, 2002). Further supporting a role for parkin in mono-, rather than polyubiquitination of PICK1, we find that steady state levels of PICK1 are not increased in whole brain, synaptic fractions, or cultured cortical neuron lysates prepared from parkin knockout mice compared with wild-type littermates.…”

Section: Discussionsupporting

confidence: 55%

Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels

Joch

Ase

Chen

et al. 2007

MBoC

128

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Mutations in the parkin gene result in an autosomal recessive juvenile-onset form of Parkinson's disease. As an E3 ubiquitin-ligase, parkin promotes the attachment of ubiquitin onto specific substrate proteins. Defects in the ubiquitination of parkin substrates are therefore believed to lead to neurodegeneration in Parkinson's disease. Here, we identify the PSD-95/Discs-large/Zona Occludens-1 (PDZ) protein PICK1 as a novel parkin substrate. We find that parkin binds PICK1 via a PDZ-mediated interaction, which predominantly promotes PICK1 monoubiquitination rather than polyubiquitination. Consistent with monoubiquitination and recent work implicating parkin in proteasome-independent pathways, parkin does not promote PICK1 degradation. However, parkin regulates the effects of PICK1 on one of its other PDZ partners, the acid-sensing ion channel (ASIC). Overexpression of wild-type, but not PDZ binding-or E3 ubiquitinligase-defective parkin abolishes the previously described, protein kinase C-induced, PICK1-dependent potentiation of ASIC2a currents in non-neuronal cells. Conversely, the loss of parkin in hippocampal neurons from parkin knockout mice unmasks prominent potentiation of native ASIC currents, which is normally suppressed by endogenous parkin in wild-type neurons. Given that ASIC channels contribute to excitotoxicity, our work provides a mechanism explaining how defects in parkin-mediated PICK1 monoubiquitination could enhance ASIC activity and thereby promote neurodegeneration in Parkinson's disease. INTRODUCTIONParkinson's disease (PD) is characterized by the selective and progressive loss of midbrain dopamine neurons resulting in motor dysfunction and disability. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism, which accounts for a large proportion of genetically linked PD cases (Kitada et al., 1998). Parkin encodes a 465-amino acid protein (ϳ52 kDa) that is expressed in multiple tissues and functions in the ubiquitin (Ub) system as an E3 Ub-ligase (Shimura et al., 2000). Ubiquitination of substrate proteins is a tightly regulated process, requiring the combined activity of three enzymes: an E1 Ub-activating enzyme, E2 Ub-conjugating enzymes, and E3 Ub-ligases (Hershko and Ciechanover, 1998). E3 Ub-ligases bind substrate proteins and therefore regulate and confer specificity to the ubiquitination reaction. Typically, ubiquitination leads to the assembly of a K48-linked polyubiquitin chain on the substrate, which targets it for degradation by the 26S proteasome, a large multimeric proteolytic complex (Voges et al., 1999). Accordingly, defects in parkin-mediated ubiquitination have been proposed to result in the failure to target parkin substrates to the proteasome for degradation (Kahle et al., 2000;Feany and Pallanck, 2003;Giasson and Lee, 2003). The ensuing accumulation of parkin substrates is believed, in turn, to induce the cellular toxicity and dopamine neuron loss seen in PD. Although numerous parkin substrates have been identified (Zhang et al., 2000;Chung et al., 2001...

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Section: Discussionsupporting

confidence: 55%

Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels

Joch

Ase

Chen

et al. 2007

MBoC

128

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“…Another emerging candidate in this regard is the ubiquitin ligase parkin, mutations in which cause early onset forms of Parkinson's disease (Kitada et al, 1998). Parkin is able to associate with Hsc/Hsp70 and displays a substrate specificity that partially overlaps with the one of CHIP (Imai et al, 2002;Tsai et al, 2003;Morishima et al, 2008). Moreover, parkin activity is under control of the Hsc/Hsp70 co-chaperone BAG-5, which further emphasizes its function as a chaperone-associated ubiquitin ligase (Kalia et al, 2004).…”

Section: Figurementioning

confidence: 99%

“…Although initially linked to proteasomal degradation (Imai et al, 2002), recent research shows that parkin is selectively recruited to dysfunctional mitochondria and triggers their disposal through selective autophagy (Narendra et al, 2008;Geisler et al, 2010). Conceivably, parkin can cooperate with the Hsc/ Hsp70 chaperone system during the recognition of damaged mitochondria that can expose unfolded proteins at their surface.…”

Section: Casa: Chaperone-assisted Selective Autophagymentioning

confidence: 99%

Chaperone-assisted degradation: multiple paths to destruction

Kettern

Dreiseidler

Tawo³

et al. 2010

Biological Chemistry

154

155

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Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP ( haperone-ssisted roteasomal degradac a p tion), CASA ( haperone-ssisted elective utophagy), and c a s a CMA ( haperone-ediated utophagy). Within these pathc m a ways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.

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“…This additional factor has been termed ''E4'' and was so far found in yeast, mouse, and human cells (100)(101)(102).…”

Section: The Ubiquitin-proteasome Systemmentioning

confidence: 99%

The proteasome and its role in the degradation of oxidized proteins

2008

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SummaryThe generation of free radicals and the resulting oxidative modification of cell structures are omnipresent in mammalian cells. This includes the permanent oxidation of proteins leading to the disruption of the protein structure and an impaired functionality. In consequence, these oxidized proteins have to be removed in order to prevent serious metabolic disturbances. The most important cellular proteolytic system responsible for the removal of oxidized proteins is the proteasomal system. For normal functioning, the proteasomal system needs the coordinated interaction of numerous components. This review describes the fundamental functions of the 20S ''core'' proteasome, its regulators, and the roles of the proteasomal system beyond the removal of oxidized proteins in mammalian cells. IUBMBIUBMB Life, 60(11): 743-752, 2008

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CHIP Is Associated with Parkin, a Gene Responsible for Familial Parkinson's Disease, and Enhances Its Ubiquitin Ligase Activity

Cited by 451 publications

References 32 publications

Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels

Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels

Chaperone-assisted degradation: multiple paths to destruction

The proteasome and its role in the degradation of oxidized proteins

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