An E3 Ubiquitin Ligase, Synoviolin, Is Involved in the Degradation of Homocysteine-Inducible Endoplasmic Reticulum Protein

Maeda, Tomoji; Fujita, Yu; Tanabe-Fujimura, Chiaki; Zou, Kun; Liu, Junjun; Kikuchi, Kota; Shen, Xiangrong; Nakajima, Takeshi; Komano, Hiroto

doi:10.1248/bpb.b18-00015

Cited by 4 publications

(4 citation statements)

References 24 publications

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“…On the other hand, while the ERAD complex component HERP protein was degraded by the UPS ( Hori et al, 2004 ), EDEM1 and ERManI proteins were eliminated by the autophagy machinery ( Le Fourn et al, 2013 ; Park et al, 2014 ; Benyair et al, 2015 ). An ER-localized E3 ligase synoviolin protein was shown to ubiquitylate HERP protein and control its degradation by proteasome ( Maeda et al, 2018 ). Yet, other ERAD-related components, EDEM1 and Derlin2 as well as ubiquitylated EDEM1 proteins colocalized with cytoplasmic aggregates and autophagy receptors p62 and NBR1, they were degraded by selective autophagy ( Le Fourn et al, 2013 ; Park et al, 2014 ).…”

Section: The Ups-autophagy Connectionmentioning

confidence: 99%

Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System

Kocatürk

Gözüaçık

2018

Front. Cell Dev. Biol.

332

268

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Autophagy and the ubiquitin–proteasome system (UPS) are the two major intracellular quality control and recycling mechanisms that are responsible for cellular homeostasis in eukaryotes. Ubiquitylation is utilized as a degradation signal by both systems, yet, different mechanisms are in play. The UPS is responsible for the degradation of short-lived proteins and soluble misfolded proteins whereas autophagy eliminates long-lived proteins, insoluble protein aggregates and even whole organelles (e.g., mitochondria, peroxisomes) and intracellular parasites (e.g., bacteria). Both the UPS and selective autophagy recognize their targets through their ubiquitin tags. In addition to an indirect connection between the two systems through ubiquitylated proteins, recent data indicate the presence of connections and reciprocal regulation mechanisms between these degradation pathways. In this review, we summarize these direct and indirect interactions and crosstalks between autophagy and the UPS, and their implications for cellular stress responses and homeostasis.

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Section: The Ups-autophagy Connectionmentioning

confidence: 99%

Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System

Kocatürk

Gözüaçık

2018

Front. Cell Dev. Biol.

332

268

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“…Among the differentially expressed proteins, SYVN1, an E3 ligase was found to be upregulated threefold in the treated cells (Figure 3A). Based on our previous studies demonstrating the ubiquitin-proteasomal degradation of MNK1/2 induced by VNLG-152R in breast (9,18) and prostate (33, 34) cancer cell lines and the role of SYVN1 as an E3 ligase involved in ubiquitination and proteasomal degradation of several proteins (35)(36)(37)(38)(39)(40)(41)(42), we hypothesized that SYVN1 might play a key role in the ubiquitination and subsequent degradation of MNK1/2. Immunoblotting for SYVN1 confirmed its increased expression in VNLG-152R-treated cells compared to the control with concomitant decrease in MNK1/2 and its product p-eIF4E (Figure 3B).…”

Section: Syvn1 Is Constitutively Upregulated In Vnlg-152r-treated Tnb...mentioning

confidence: 99%

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.

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“…For example, it was shown that one of the main agents contributing to the accumulation of Aβ and tau proteins is homocysteine (Shirafuji et al , 2018). Homocysteine triggers the endoplasmic reticulum protein HERP, stimulating the c-secretase activity and increasing Aβ accumulation in the brain (Maeda et al , 2018). In hyperlipidemia, diabetes, hypertension, etc., the brain exposes to ischemic and hypoxic conditions (Cheng et al , 2018), which impairs the blood and cerebrospinal fluid flow and decreases aggregated proteins clearance.…”

Section: Dementia Risk Factorsmentioning

confidence: 99%

The comprehensive mechanistic insight into the effects of vitamin D on dementia – a review

Jafarzadeh¹,

Payahoo

Yousefi

et al. 2021

NFS

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Purpose This paper aims to depict the mechanistic role of vitamin D on dementia prevention, relief of the severity and the complication of the disease. All papers indexed in scientific databases, including Scopus, Elsevier, PubMed, Embase and Google Scholar between 2000 and 2021 were extracted and discussed. To present the mechanistic role of vitamin D in declining the severity of dementia, keywords including dementia, vitamin D, oxidative stress, inflammation, amyloid beta-Peptides were used. Design/methodology/approach Dementia is a prevalent cognitive disorder worldwide, especially in elderly people, which is accompanied by serious disabilities. Besides genetic, biological and lifestyle factors are involved in the incidence of dementia. An unhealthy diet along with micronutrient deficiencies are among modifiable factors. Vitamin D is one of the important micronutrients in brain health. Besides the involvement in gene expression, bone mineralization, apoptosis, inflammation, skeletal maturation, neurotropic action and hemostasis of phosphate and calcium, vitamin D also exerts neuroprotective effects via genomic and non-genomic pathways. Findings Vitamin D up-regulates the expression of various genes involved in dementia incidence via various mechanisms. Decreasing oxidative stress and the neuro-inflammatory cytokines levels, regulation of the expression of alternated Proteins including Tau and Amyloid-ß, calcium homeostasis in the central nervous system and also vascular are considered main mechanisms. Originality/value Considering the importance of diet in preventing dementia, adherence to a healthy diet that provides essential nutrients to brain function seems to be urgent. Controlling serum levels of vitamin D periodically and providing vitamin D by related sources or supplements, if there is a deficiency, is recommended. Future studies are needed to clarify other related mechanisms.

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An E3 Ubiquitin Ligase, Synoviolin, Is Involved in the Degradation of Homocysteine-Inducible Endoplasmic Reticulum Protein

Cited by 4 publications

References 24 publications

Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System

Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

The comprehensive mechanistic insight into the effects of vitamin D on dementia – a review

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