Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Chin, Lih‐Shen; Vavalle, John P.; Lian, Li

doi:10.1074/jbc.m203300200

Cited by 110 publications

(87 citation statements)

References 66 publications

(60 reference statements)

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“…Subcellular Fractionation-Subcellular fractionation was performed as previously described (36,44,45). SH-SY5Y cells were collected by centrifugation and the pellet was homogenized in 1 ml of homogenization buffer (250 mM sucrose, 10 mM HEPES/KOH, pH 7.4, 10 mM KCl, 0.1 mM EGTA, 0.1 mM EDTA) containing protease inhibitors and dithiothreitol.…”

Section: Methodsmentioning

confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

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Section: Methodsmentioning

confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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“…In multicellular organisms, two copies of the BRE1 protein are present, such as STARING and XP_232995 in rat (Ratus norvegicus) (Chin et al, 2002) and RNF40 and RNF20 in human (Zhu et al, 2005). In Arabidopsis, another BRE1 homolog belonging to the same class of RING finger proteins has also been identified by Chin et al (2002) as an 899-amino acid protein (At1g55250) and a shorter 384-amino acid protein (At1g55255) by Stone et al (2005). Although the annotation of At1g55250 and At1g55255 as two different genes was supported by The Institute for Genome Research and The Arabidopsis Information Resource, we suspected annotation errors based on sequence homology to At2g44950.…”

Section: Hub1 and Its Homolog Encode Ring Finger Proteins Orthologoumentioning

confidence: 99%

TheArabidopsis thalianaHomolog of YeastBRE1Has a Function in Cell Cycle Regulation during Early Leaf and Root Growth

et al. 2007

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Chromatin modification and transcriptional activation are novel roles for E3 ubiquitin ligase proteins that have been mainly associated with ubiquitin-dependent proteolysis. We identified HISTONE MONOUBIQUITINATION1 (HUB1) (and its homolog HUB2) in Arabidopsis thaliana as RING E3 ligase proteins with a function in organ growth. We show that HUB1 is a functional homolog of the human and yeast BRE1 proteins because it monoubiquitinated histone H2B in an in vitro assay. Hub knockdown mutants had pale leaf coloration, modified leaf shape, reduced rosette biomass, and inhibited primary root growth. One of the alleles had been designated previously as ang4-1. Kinematic analysis of leaf and root growth together with flow cytometry revealed defects in cell cycle activities. The hub1-1 (ang4-1) mutation increased cell cycle duration in young leaves and caused an early entry into the endocycles. Transcript profiling of shoot apical tissues of hub1-1 (ang4-1) indicated that key regulators of the G2-to-M transition were misexpressed. Based on the mutant characterization, we postulate that HUB1 mediates gene activation and cell cycle regulation probably through chromatin modifications.

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“…Syntaxin 1 is a presynaptic protein that has a role in synaptic vesicle exocytosis. Evidence for ubiquitin-proteasome-mediated degradation of syntaxin 1 was obtained through identification of an ubiquitin ligase called staring (syntaxin 1-interacting RING finger protein) using the yeast two-hybrid system (Chin et al 2002). Coexpression of staring with syntaxin 1 in HeLa cells increases the degradation of syntaxin 1, which can be inhibited by the proteasome inhibitor MG132.…”

Section: Presynaptic Roles Of the Uppmentioning

confidence: 99%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

129

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Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

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Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Cited by 110 publications

References 66 publications

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

TheArabidopsis thalianaHomolog of YeastBRE1Has a Function in Cell Cycle Regulation during Early Leaf and Root Growth

The ubiquitin-proteasome pathway and synaptic plasticity

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