Cell Death & Disease
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2018
·Vol. 9
·期 10
·1-16
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IF 5.638
Niu Xiuran,Su Linjia,Qi Shanshan,Gao Zhihui,Zhang Qing,Zhang Sihe
Chaperone-assisted proteasome degradation of oncogenic protein acts as an upstream signal controlling tumorigenesis and progression. The understanding of the co-regulation of chaperone and oncoprotein of endocytosis pathways is extremely limited. In this study, we showed for the first time that proto-Dbl ( dbl proto-oncogene product) is co-enriched with mitochondrial chaperone GRP75 in endocytosis vesicles from ovarian cancer cells. onco-Dbl, produced by oncogenic mutation/degradation of proto-Dbl, markedly enhanced cellular macropinocytosis but suppressed clathrin-mediated endocytosis and clathrin-independent endocytosis pathways, presenting a derailed endocytosis phenotype. GRP75 was associated with proto-Dbl inside cells and modulated Dbl-driven endocytosis derailed by a co-regulatory mode. In spite of not being a component of the Hsc70/Hsp90/proto-Dbl complex, the degradation of proto-Dbl was promoted by GRP75 through the CHIP-mediated ubiquitin–proteasome pathway, of which GRP75 acts as a cooperator with CHIP but also acts as a competitor to Hsc70 and Hsp90 in the multiple chaperones-assisted pro-folding/pro-degradation machinery. Knockdown or inhibition of GRP75 attenuated proto-Dbl degradation and reduced the onco-Dbl level, which differentially impaired Rho GTPases activation and therefore shifted the endocytosis-derailed phenotype. Our data uncovered a novel GRP75-Dbl endocytosis regulatory axis and provided an alternative using chaperone inhibitor to shut down the oncoprotein-driven endocytosis derailment mechanism.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2019
·
IF 3.775
Xuan Yang,Yijia Li,Lirong Zheng,Xiaoyun He,Yunbo Luo,Kunlun Huang,Wentao Xu
The incidence of kidney disease has increased rapidly in recent years. One major possible reason for this increase in nephrosis is from foodborne toxins. Since the mechanism of how foodborne toxins are involved in the process of nephrosis is largely unknown, the current study aims to establish a profile for how one of the major toxin threats, ochratoxin A (OTA), induce differential protein expression. In this proteomic study of rat kidneys, 75 kd glucose-regulated protein (Grp75) expression was found to be sensitized by a low concentration of OTA, but inhibited by high doses. In response to OTA, a decrease in Grp75 expression preceded the inhibition of mitochondrial Lon peptidase 1 (Lonp1). Using Grp75 knockdown cell line, it was shown that the inhibition of Grp75 promoted the secretion of kidney injury molecule 1 (Kim1), and suppressed Lonp1 expression in renal injury . Moreover, the acceleration of renal disease was associated with the consumption of Grp75. Our study suggests that the Grp75 protein may be valuable as both a treatment and biomarker for the foodborne diseases that induce renal tubular necrosis . The findings of this research are beneficial for the establishment of nutritional interventions, and the screening of therapeutic targets, in cases of nephrosis.
研究领域:
毒理学
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肾病学
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蛋白质组学
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食品安全
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Fengying Shao,Jianyu Han,Zhaoyan Tian,Zhi Wang,Songqin Liu,Yafeng Wu
Taking advantage of endogenous Ca 2+ to upregulate intramitochondrial Ca 2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca 2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca 2+ transport. It remains a great challenge to make the maximum use of endogenous Ca 2+ to ensure sufficient Ca 2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca 2+ directional transport channel to selectively transport endogenous Ca 2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@Fe III -tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment , Fe 3+ ions are firstly released and reduced by tannic acid (TA) to Fe 2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca 2+ ions are directionally delivered and intramitochondrial Ca 2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca 2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca 2+ -involved tumor therapies.
研究领域:
肿瘤学
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Junke Wang,Yuexin Wei,Yuhao Wu,Tianxin Zhao,Lian Kang,Lindong Han,Jiadong Chen,Chunlan Long,Guanghui Wei,Lianju Shen,Shengde Wu
As one of the most prevalent environmental endocrine disruptors, di-(2-ethylhexyl) phthalate (DEHP) is known for its significant developmental toxicity to the male reproductive system in humans and mice. Prepubertal exposure to DEHP has been shown to cause testicular damage, but the underlying mechanisms require further investigation. To investigate this effect, prepubertal mice were exposed to 250 or 500 mg/kg body weight (bw) of DEHP for 14 days, which resulted in impaired histological structure and increased apoptosis of the testes. RNA sequencing (RNA-seq) of testicular tissue suggested that DEHP led to injury in Leydig and Sertoli cells. To further elucidate these mechanisms, we conducted experiments using immature mouse Leydig (TM3) and Sertoli (TM4) cells, and exposed them to 200 μM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, for 24 h. We found that MEHP exposure induced oxidative stress injury and promoted cell apoptosis, and that cotreatment with N-acetylcysteine partially reversed these injuries. Given the close association between oxidative stress and mitochondrial calcium levels, we demonstrated that MEHP exposure disrupted mitochondria and increased mitochondrial calcium levels. This effect facilitated the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), upregulated protein expression and enhanced the interactions of the IP3R3-Grp75-VDAC1 complex. Furthermore, inhibition of calcium transfer in the IP3R3-Grp75-VDAC1-MCU axis relieved MEHP-induced mitochondrial injury, oxidative stress and apoptosis in TM3 and TM4 cells. This study highlights the importance of MAM-mediated mitochondrial calcium overload and the subsequent apoptosis of Leydig and Sertoli cells as pivotal factors contributing to testicular injury induced by prepubertal exposure to DEHP.
研究领域:
环境科学
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毒理学
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生殖生物学
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细胞生物学
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内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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