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TRIM69 inhibits cataractogenesis by negatively regulating p53.

ABSTRACT: Ultraviolet B (UVB) irradiation can induce reactive oxygen species (ROS) production and apoptosis in human lens epithelial cells (HLECs), thus leading to the formation of cataracts. We studied the role of tripartite motif 69 (TRIM69) in cataract formation. The expression of TRIM69 protein was down-regulated in both human cataract capsule tissues and HLECs treated with UVB, whereas the expression of p53 protein exhibited an opposite trend. Ectopic expression of TRIM69 in HLECs significantly suppressed UVB-induced apoptosis and ROS production, whereas knockdown of TRIM69 promoted apoptosis and ROS production. TRIM69 can interact with p53 and induce its ubiquitination. The effects of TRIM69 overexpression in UVB-induced cell apoptosis and ROS production was clearly weakened by p53 overexpression, thus suggesting a role for p53 in TRIM69 functions. Furthermore, inhibition of ROS mitigated the effects of UVB irradiation on ROS production, cell apoptosis, forkhead box protein 3a (Foxo3a) phosphorylation, and TRIM69 expression. Additionally, Foxo3a overexpression significantly enhanced TRIM69 promoter activity, whereas Foxo3a knockdown had the opposite effect. In conclusion, we provide the first demonstration that Foxo3a is a potential transcription factor for TRIM69, and TRIM69 induces p53 ubiquitination. These results suggest that the Foxo3a/TRIM69/p53 regulatory network may be involved in cataract formation.

SUBMITTER: Rong X

PROVIDER: S-EPMC6402377 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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TRIM69 inhibits cataractogenesis by negatively regulating p53.

Rong Xianfang X Rao Jun J Li Dan D Jing Qinghe Q Lu Yi Y Ji Yinghong Y

Redox biology 20190302

Ultraviolet B (UVB) irradiation can induce reactive oxygen species (ROS) production and apoptosis in human lens epithelial cells (HLECs), thus leading to the formation of cataracts. We studied the role of tripartite motif 69 (TRIM69) in cataract formation. The expression of TRIM69 protein was down-regulated in both human cataract capsule tissues and HLECs treated with UVB, whereas the expression of p53 protein exhibited an opposite trend. Ectopic expression of TRIM69 in HLECs significantly suppr ...[more]

PMID: 30844644

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Project description:Vesicular stomatitis Indiana virus (VSIV), formerly known as vesicular stomatitis virus (VSV) Indiana (VSVIND), is a model virus that is exceptionally sensitive to the inhibitory action of interferons (IFNs). Interferons induce an antiviral state by stimulating the expression of hundreds of interferon-stimulated genes (ISGs). These ISGs can constrain viral replication, limit tissue tropism, reduce pathogenicity, and inhibit viral transmission. Since VSIV is used as a backbone for multiple oncolytic and vaccine strategies, understanding how ISGs restrict VSIV not only helps in understanding VSIV-induced pathogenesis but also helps us evaluate and understand the safety and efficacy of VSIV-based therapies. Thus, there is a need to identify and characterize the ISGs that possess anti-VSIV activity. Using arrayed ISG expression screening, we identified TRIM69 as an ISG that potently inhibits VSIV. This inhibition was highly specific as multiple viruses, including influenza A virus, HIV-1, Rift Valley fever virus, and dengue virus, were unaffected by TRIM69. Indeed, just one amino acid substitution in VSIV can govern sensitivity/resistance to TRIM69. Furthermore, TRIM69 is highly divergent in human populations and exhibits signatures of positive selection that are consistent with this gene playing a key role in antiviral immunity. We propose that TRIM69 is an IFN-induced inhibitor of VSIV and speculate that TRIM69 could be important in limiting VSIV pathogenesis and might influence the specificity and/or efficacy of vesiculovirus-based therapies.IMPORTANCE Vesicular stomatitis Indiana virus (VSIV) is a veterinary pathogen that is also used as a backbone for many oncolytic and vaccine strategies. In natural and therapeutic settings, viral infections like VSIV are sensed by the host, and as a result the host cells make proteins that can protect them from viruses. In the case of VSIV, these antiviral proteins constrain viral replication and protect most healthy tissues from virus infection. In order to understand how VSIV causes disease and how healthy tissues are protected from VSIV-based therapies, it is crucial that we identify the proteins that inhibit VSIV. Here, we show that TRIM69 is an antiviral defense that can potently and specifically block VSIV infection.

Project description:ObjectiveTo investigate the effects of miR-300 and PTTG1 on osteosarcoma invasion and metastasis and explore the molecular mechanism of osteosarcoma invasion and metastasis.ObjectiveWestern blot was used to detect the expression of PTTG1 in human osteoblasts hFOB1.19 and osteosarcoma cell MG63 and to detect the transfection efficiency of cells transfected with PTTG1-knockdown plasmid; Transwell invasion assay and CCK8 assay detected the effects of knockdown of PTTG1 and overexpression of miR-300 on the invasion and proliferation of osteosarcoma cell MG63. On-line prediction and screening of microRNAs (miRNAs) with complementary PTTG1 binding was conducted. qRT-PCR was performed to examine the expression of miR-300 in hFOB1.19 and MG63 cells, and Western blotting was used to detect the expression of PTTG1 in MG63 cells after transfection with a miR- 300 plasmid. Double luciferase assay was used to detect the targeted binding of miR-300 and PTTG, Transwell invasion assay and CCK8 assay were used to detect the effects of overexpression of miR-300 and overexpression of PTTG1 plasmid on invasion and proliferation of osteosarcoma cell line MG63.ObjectivePTTG1 was highly expressed in MG63 cells (P=0.0002). PTTG1 knockdown significantly inhibited the invasion (P=0.0002) and proliferation (P=0.0039) of MG63 cells. Based on the results of online prediction of complementary miRNAs to PTTG1 and analysis of the data from NCBI database, miR-300 was determined as the target miRNA in this study. qRT-PCR results showed a significantly decreased expression of miR-300 in MG63 cells (P=0.0004). Overexpression of MiR-300 in MG63 cells significantly decreased the expression of PTTG1 (P=0.0007), and the expressions of miR-300 and PTTG1 were negatively correlated. Dual luciferase assay showed that miR-300 could specifically bind to PTTG1 (P=0.001). Overexpression of PTTG1 could significantly reverse the effect of miR-300 overexpression on invasion (P=0.0003) and proliferation (P=0.0077) of MG63 cells.ObjectiveOverexpression of miR-300 can inhibit the invasion and metastasis of osteosarcoma cell MG63 by targeting PTTG1.

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TRIM69 inhibits cataractogenesis by negatively regulating p53.

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TRIM69 inhibits cataractogenesis by negatively regulating p53.

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