The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration

Corti, Olga; Hampe, Christiane S.; Koutníková, Hana; Darios, Frédéric; Jacquier, Sandrine; Prigent, Annick; Robinson, Jean-Charles; Pradier, Laurent; Ruberg, Merle; Mirande, Marc; Hirsch, Étienne C.; Rooney, Thomas; Fournier, Alain; Brice, Alexis

doi:10.1093/hmg/ddg159

Cited by 228 publications

(146 citation statements)

References 59 publications

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“…Next, the effects of c-Abl on parkin ubiquitination of AIMP2 were monitored. Parkin ubiquitinates AIMP2 as previously described (8,20) and Y143F parkin also ubiquitinates AIMP2 (Fig. 3C).…”

Section: Resultssupporting

confidence: 79%

Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function

Ko¹,

Lee²,

Shin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

247

291

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Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin E3 ligase activity and protective function. c-Abl is activated by dopaminergic stress and by dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP + ) in vitro and in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation of the parkin substrates aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FBP1), and cell death. STI-571, a c-Abl-family kinase inhibitor, prevents the phosphorylation of parkin, maintaining parkin in a catalytically active and protective state. STI-571's protective effects require parkin, as shRNA knockdown of parkin prevents STI-571 protection. Conditional knockout of c-Abl in the nervous system also prevents the phosphorylation of parkin, the accumulation of its substrates, and subsequent neurotoxicity in response to MPTP intoxication. In human postmortem PD brain, c-Abl is active, parkin is tyrosine-phosphorylated, and AIMP2 and FBP1 accumulate in the substantia nigra and striatum. Thus, tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modification that inhibits parkin function, possibly contributing to pathogenesis of sporadic PD. Moreover, inhibition of c-Abl may be a neuroprotective approach in the treatment of PD.is a common neurodegenerative disorder characterized by the loss of dopamine (DA) neurons and protein accumulation in intracellular inclusions designated as Lewy bodies and Lewy neurites (1). Although the majority of PD is sporadic in nature, rare familial mutations are providing insight into this chronic, progressive neurodegenerative disease. Mutations in α-synuclein and LRRK2 cause autosomal-dominant PD, whereas mutations in DJ-1, PINK1, and parkin result in autosomal-recessive PD (2). Parkin mutations are the most common cause of autosomal-recessive PD and, for the most part, PD due to parkin mutations is indistinguishable from sporadic PD (3). Parkin is a ubiquitin E3 ligase, and familial mutations are thought to impair the E3 ligase activity of parkin (4, 5).Parkin ubiquitinates proteins via monoubiquitination or polyubiquitination using either lysine 48 (K48) or lysine 63 (K63). Monoubiquitination by parkin is thought to regulate receptor trafficking (6). Polyubiquitination by parkin via K48 is thought to mediate proteasomal degradation (7,8), whereas polyubiquitination by K63 may be involved in inclusion formation (9). Parkin's differential ubiquitination properties are likely to be regulated by different ubiquitin-conjugating E2s and other associated proteins or regulatory processes (3). A number of putative parkin substrates have been identified (for a review, see ref.3). Aminoacyl-tRNA synthetaseinteracting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FB...

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“…Next, the effects of c-Abl on parkin ubiquitination of AIMP2 were monitored. Parkin ubiquitinates AIMP2 as previously described (8,20) and Y143F parkin also ubiquitinates AIMP2 (Fig. 3C).…”

Section: Resultssupporting

confidence: 79%

Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function

Ko¹,

Lee²,

Shin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

247

291

View full text Add to dashboard Cite

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“…S-nitrosylation of parkin inhibits its ubiquitination and protective function (Chung et al, 2004;Yao et al, 2004); thus, accumulation of parkin substrates may also contribute to the neurodegeneration in sporadic PD. A number of parkin substrates have been identified including, CDCrel-1, CDCrel-2, synphilin-1, glycosylated ␣-synuclein, ␤-tubulin, cyclin E, synaptotamin XI (SytXI), parkin-associated endothelin-like receptor (Pael-R), and p38/JTV-1 subunit of the multi-tRNA synthetase complex (Zhang et al, 2000;Chung et al, 2001;Imai et al, 2001;Shimura et al, 2001;Choi et al, 2003;Corti et al, 2003;Huynh et al, 2003;Ren et al, 2003;Staropoli et al, 2003;Jiang et al, 2004). CDCrel-1, CDCrel-2, Pael-R, and cyclin E appear to be upregulated in AR-JP brains (Imai et al, 2001;Choi et al, 2003;Staropoli et al, 2003), but none of these substrates have been reported to be upregulated in parkin knockout (KO) mice.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death

Ko¹,

Coelln²,

Sriram³

et al. 2005

J. Neurosci.

224

197

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Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-␣ treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.

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Section: Introductionmentioning

confidence: 99%

“…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;Imai et al, 2001;Corti et al, 2003;Staropoli et al, 2003), there is still controversy as to which of these accumulate in the brains of parkin knockout (KO) mice (Goldberg et al, 2003;Itier et al, 2003;Von Coelln et al, 2004;Ko et al, 2005;Perez and Palmiter, 2005;Periquet et al, 2005) and as to their respective roles in the pathogenesis of PD (Cookson, 2005;Moore et al, 2005).In addition to its traditional role, Ub can serve as a reversible posttranslational modification that regulates the function of tagged proteins without necessarily leading to their destruction by the proteasome (Hicke and Dunn, 2003;Mukhopadhyay and Riezman, 2007). Depending on the length and architecture of the Ub chain, ubiquitination has been implicated in a variety of cellular functions as diverse as signal transduction, transcription, and membrane trafficking (Mukhopadhyay and Riezman, 2007).…”

mentioning

confidence: 99%

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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The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration

Cited by 228 publications

References 59 publications

Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function

Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function

Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death

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

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