Dysbindin-Associated Proteome in the P2 Synaptosome Fraction of Mouse Brain

Han, Meng-Hsuan; Hu, Zhonghua; Chen, Cai Yun; Chen, Yong; Guček, Marjan; Li, Zheng; Markey, Sanford P.

doi:10.1021/pr500656z

Cited by 12 publications

(8 citation statements)

References 72 publications

(186 reference statements)

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“…Furthermore, high levels of WDR11 are found in the brains of embryonic and adult mice (35), and disruptions to WDR11 are associated with IHH/KS/CPHD (35,38), conditions that result from abnormal migration of specific neurons during embryogenesis (reviewed in reference 101). Additionally, WDR11 interacts with dysbindin, a neuronal protein enriched in synapses (102), as well as EMX1 (35), a protein with important functions in the developing nervous system (reviewed in reference 103). Therefore, it is possible that the function of WDR11 may be more crucial for viral replication in vivo in neurons as opposed to cells of the periphery.…”

Section: Discussionmentioning

confidence: 99%

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Taylor

Mossman

2015

J Virol

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It has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to the transGolgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment. IMPORTANCEWhile the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV. W ith worldwide seroprevalence rates reaching 60 to 90% (1), herpes simplex virus 1 (HSV-1) is a tremendously successful human pathogen. HSV-1 particles consist of a double-stranded DNA genome encased by an icosahedral capsid, surrounded by a proteinaceous layer known as the tegument, which is in turn enclosed by an envelope of host-derived lipids (2). During the lytic replication cycle, viral glycoprotein-mediated fusion of the envelope with the host cell plasma membrane releases the capsid and tegument proteins into the cytosol (3). HSV capsids are then transported to the nucleus along microtubules via molecular motor proteins (4). The release of the genome into the nucleus is followed by viral gene expression in a sequential manner, beginning with the immediate-early (IE) genes and then progressing to the early (E) and late (L) classes, resulting in viral genomic DNA replication and packaging into capsids.Although subsequent steps have been controversial, it is n...

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Section: Discussionmentioning

confidence: 99%

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Taylor

Mossman

2015

J Virol

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“…Annotation of these proteins to neuronal functions indicates that in a majority they are involved in neurotransmitter vesicle fusion and synaptic plasticity [ 102 ]. Additional quantitative proteomic studies have identified changes in expression of proteins and polypeptides sensitive to dysbindin/BLOC-1 loss of function, including: (i) the BLOC-1 subunits, such as Bloc1s1-5 and snapin; (ii) dynactin complex, such as alpha-centractin and dynactin 2; (iii) exocyst complex, such as exocyst 3 and exocyst 4; (iv) tubulin/actin associated proteins, such as actin alpha 1 and tubulin alpha 1b; (v) AP3 complex, such as adaptor-related protein complex-3B1 and -2; (vi) vesicular transport/trafficking associated/fusion apparatus, such as adaptor protein 2A1, the vesicle associated membrane protein 7, syntaxin-binding protein 1 and 5; (vii) proteasome subunits, such as proteasome modulator 9 and proteasome subunit alpha type 4; and (viii) other proteins, such as the copper-transporting P-type adenosine triphosphatase (ATP7A), the N -ethymaleimide-sensitive factor, annexin A2, syntaxin 7 and 17, synaptosomal-associated protein 25 and family with sequence similarity 91 member A1 [ 95 , 98 , 102 , 103 , 104 ]. Future investigations on these dysbindin-1-interacting proteins are expected to expand dysbindin-1 neuronal functions and provide alternative, additional molecular targets for schizophrenia susceptibility.…”

Section: Dysbindin-1 Is Required For Diverse Presynaptic and Postsmentioning

confidence: 99%

Dysbindin-1 Involvement in the Etiology of Schizophrenia

Wang

Lazarovici

Zheng

2017

IJMS

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Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world’s population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

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“…The proteasome is essential for the development and function of numerous organs and structures of the human body [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. Thus, reduced activity of the cilia-regulated proteasome is a possible cause of ciliopathies.…”

Section: The Cilia-regulated Proteasome Is Essential For Gli Procementioning

confidence: 99%

Control of Hedgehog Signalling by the Cilia-Regulated Proteasome

Gerhardt

Wiegering

Leu

et al. 2016

JDB

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The Hedgehog signalling pathway is evolutionarily highly conserved and essential for embryonic development of invertebrates and vertebrates. Consequently, impaired Hedgehog signalling results in very severe human diseases, ranging from holoprosencephaly to Pallister-Hall syndrome. Due to this great importance for human health, the focus of numerous research groups is placed on the investigation of the detailed mechanisms underlying Hedgehog signalling. Today, it is known that tiny cell protrusions, known as primary cilia, are necessary to mediate Hedgehog signalling in vertebrates. Although the Hedgehog pathway is one of the best studied signalling pathways, many questions remain. One of these questions is: How do primary cilia control Hedgehog signalling in vertebrates? Recently, it was shown that primary cilia regulate a special kind of proteasome which is essential for proper Hedgehog signalling. This review article will cover this novel cilia-proteasome association in embryonic Hedgehog signalling and discuss the possibilities provided by future investigations on this topic.

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Dysbindin-Associated Proteome in the P2 Synaptosome Fraction of Mouse Brain

Cited by 12 publications

References 72 publications

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Dysbindin-1 Involvement in the Etiology of Schizophrenia

Control of Hedgehog Signalling by the Cilia-Regulated Proteasome

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