Dataset Information

SYVN1, an ERAD E3 Ubiquitin Ligase, Is Involved in GABAA?1 Degradation Associated with Methamphetamine-Induced Conditioned Place Preference.

ABSTRACT: Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABAA?1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr. The siRNA knockdown of SYVN1 significantly increased GABAA?1 protein levels in both primary cultured neurons and rodent Dstr. Inhibition of proteasomal activity by MG132 and Lactacystin significantly increased GABAA?1 protein levels. We further found that SYVN1 knockdown increased GABAA?1 in the intra-ER, but not in the extra-ER. Accordingly, endoplasmic reticulum stress (ERS)-associated Glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) increased. Thus, this study revealed that SYVN1, as the ERAD E3 ubiquitin ligase, was associated with Dstr GABAA?1 degradation induced by METH conditioned pairing.

SUBMITTER: Jiao DL

PROVIDER: S-EPMC5633679 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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SYVN1, an ERAD E3 Ubiquitin Ligase, Is Involved in GABA<sub>A</sub>α1 Degradation Associated with Methamphetamine-Induced Conditioned Place Preference.

Jiao Dong-Liang DL Chen Yan Y Liu Yao Y Ju Yun-Yue YY Long Jian-Dong JD Du Jiang J Yu Chang-Xi CX Wang Yu-Jun YJ Zhao Min M Liu Jing-Gen JG

Frontiers in molecular neuroscience 20171005

Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABA<sub>A</sub>α1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was uncl ...[more]

PMID: 29051727

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Project description:BackgroundTumor metastasis is a major factor for poor prognosis of hepatocellular carcinoma (HCC), but the relationship between ubiquitination and metastasis need to be studied more systematically. We analyzed the ubiquitinome of HCC in this study to have a more comprehensive insight into human HCC metastasis.MethodsThe protein ubiquitination levels in 15 HCC specimens with vascular invasion and 15 without vascular invasion were detected by ubiquitinome. Proteins with significantly different ubiquitination levels between HCCs with and without vascular invasion were used to predict E3 ubiquitin ligases associated with tumor metastasis. The topological network of protein substrates and corresponding E3 ubiquitin ligases was constructed to identify the key E3 ubiquitin ligase. Besides, the growth, migration and invasion ability of LM3 and HUH7 hepatoma cell lines with and without SYVN1 expression interference were measured by cell proliferation assay, subcutaneous tumor assay, umphal vein endothelium tube formation assay, transwell migration and invasion assays. Finally, the interacting proteins of SYVN1 were screened and verified by protein interaction omics, immunofluorescence, and immunoprecipitation. Ubiquitin levels of related protein substrates in LM3 and HUH7 cells were compared in negative control, SYVN1 knockdown, and SYVN1 overexpression groups.ResultsIn this study, our whole-cell proteomic dataset and ubiquitinomic dataset contained approximately 5600 proteins and 12,000 ubiquitinated sites. We discovered increased ubiquitinated sites with shorter ubiquitin chains during the progression of HCC metastasis. In addition, proteomic and ubiquitinomic analyses revealed that high expression of E3 ubiquitin-protein ligase SYVN1 is related with tumor metastasis. Furthermore, we found that SYVN1 interacted with heat shock protein 90 (HSP90) and impacted the ubiquitination of eukaryotic elongation factor 2 kinase (EEF2K).ConclusionsThe ubiquitination profiles of HCC with and without vascular invasion were significantly different. SYVN1 was the most important E3 ubiquitin-protein ligase responsible for this phenomenon, and it was related with tumor metastasis and growth. Therefore, SYVN1 might be a potential therapeutic target for HCC.

Project description:Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains unclear. Our recent research has identified a specific subpopulation of choline acetyltransferase (ChAT+) neurons localized in the external lateral portion of parabrachial nucleus (eLPBChAT), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and functional roles of eLPBChAT projections in METH withdrawal anxiety and primed reinstatement were further explored. Methods: In the present study, a multifaceted approach was employed to dissect the LPBChAT+ projections in male mice, including anterograde and retrograde tracing, acetylcholine (Ach) indicator combined with fiber photometry recording, photogenetic and chemogenetic regulation, as well as electrophysiological recording. METH withdrawal anxiety-like behaviors and METH-primed reinstatement of conditioned place preference (CPP) were assessed in male mice. Results: We identified that eLPBChAT send projections to PKCδ-positive (PKCδ+) neurons in lateral portion of central nucleus of amygdala (lCeAPKCδ) and oval portion of bed nucleus of the stria terminalis (ovBNSTPKCδ), forming eLPBChAT-lCeAPKCδ and eLPBChAT-ovBNSTPKCδ pathways. At least in part, the eLPBChAT neurons positively innervate lCeAPKCδ neurons and ovBNSTPKCδ neurons through regulating synaptic elements of presynaptic Ach release and postsynaptic nicotinic acetylcholine receptors (nAChRs). METH withdrawal anxiety and METH-primed reinstatement of CPP respectively recruit eLPBChAT-lCeAPKCδ pathway and eLPBChAT-ovBNSTPKCδ pathway in male mice. Conclusion: Our findings put new insights into the complex neural networks, especially focusing on the eLPBChAT projections. The eLPBChAT is a critical node in the neural networks governing METH withdrawal anxiety and primed-reinstatement of CPP through its projections to the lCeAPKCδ and ovBNSTPKCδ, respectively.

Dataset Information

SYVN1, an ERAD E3 Ubiquitin Ligase, Is Involved in GABAA?1 Degradation Associated with Methamphetamine-Induced Conditioned Place Preference.

Publications

SYVN1, an ERAD E3 Ubiquitin Ligase, Is Involved in GABA<sub>A</sub>α1 Degradation Associated with Methamphetamine-Induced Conditioned Place Preference.

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