The Expression of TRIM6 Activates the mTORC1 Pathway by Regulating the Ubiquitination of TSC1-TSC2 to Promote Renal Fibrosis

Abstract

Renal fibrosis is considered as the final pathway of all types of kidney diseases, which can lead to the progressive loss of kidney functions and eventually renal failure. The mechanisms behind are diversified, in which the mammalian target of rapamycin (mTOR) pathway is one of the most important regulatory pathways that accounts for the disease. Several processes that are regulated by the mTOR pathway, such as autophagy, epithelial-mesenchymal transition (EMT), and endoplasmic reticulum (ER) stress, are tightly associated with renal fibrosis. In this study, we have reported that the expression of tripartite motif-containing (TRIM) protein 6, a member of TRIM family protein, was highly expressed in renal fibrosis patients and positively correlated with the severity of renal fibrosis. In our established in vitro and in vivo renal fibrosis models, its expression was upregulated by the Angiotensin II-induced nuclear translocation of nuclear factor-κB (NF-κB) p50 and p65. In HK2 cells, the expression of TRIM6 promoted the ubiquitination of tuberous sclerosis proteins (TSC) 1 and 2, two negative regulators of the mTORC1 pathway. Moreover, the knockdown of TRIM6 was found efficient for alleviating renal fibrosis and inhibiting the downstream processes of EMT and ER in both HK2 cells and 5/6-nephrectomized rats. Clinically, the level of TRIM6, TSC1/2, and NF-κB p50 was found closely related to renal fibrosis. As a result, we have presented the first study on the role of TRIM6 in the mTORC1 pathway in renal fibrosis models and our findings suggested that TRIM6 may be a potential target for the treatment of renal fibrosis.

Tripartite Motif Protein 6 Promotes Colorectal Cancer Cell Migration and Metastasis via SOCS2-STAT3 Signaling

“…Epithelial-mesenchymal transition (EMT) is strongly implicated in tumor cell migration, invasion, and metastasis ( 35 ). Snail1 and Twist1, two markers of EMT, and MMP2, a marker of invasion and migration, which could degrade the extracellular matrix, were downregulated in TRIM6 knockdown CRC cells, which is consistent with a study on TRIM6 in renal fibrosis ( 36 ). In this perspective, TRIM6 stimulates the EMT and production of MMP2, which could facilitate tumor cell migration, invasion, and metastasis, thus, causes tumor recurrence.…”

“…TRIM family proteins are reported to have a E3 ubiquitin ligase activity ( 38 ). Recent studies have reported that TRIM6 promoted the ubiquitination of TIS21 ( 16 ) and TSC1-TSC2 ( 36 ). TRIM6 interacts with SOCS2, and the level of SOCS2 ubiquitination was lower in TRIM6 knockdown HCT116 cells ( Figure 4 ), whereas the ubiquitination site on SOCS2 is to be identified.…”

Everolimus-Induced Loss of Exosomal miR-7-5p Activates MNK/eIF4E Axis in Non-Small Cell Lung Cancer

“…1g), which indicated that Everolimus induced the secretion of miR-7-5p-loaded exosomes into the surrounding extracellular environment, resulting in the loss of miR-7-5p in intracellular. Furthermore, we performed siTSC1/2 to active 13 but Everolimus to inhibit the activity of mTORC1. After con rming the expression of mTOR, TSC1 and TSC2 following indicated treatments (Figure S1b), we discovered miR-7-5p was more enriched in exosomes than in intracellular when Everolimus was employed.…”

Exosome-Mediated miR-7-5p Delivery Enhances the Anticancer Effect of Everolimus via Blocking MNK/eIF4E Axis in Non-Small Cell Lung Cancer

“…Furthermore, we performed siTSC1/2 to active [22] but Everolimus to inhibit the activity of mTORC1. After con rming the expression of mTOR, TSC1 and TSC2 following indicated treatments (Figure S1B), we found that miR-7-5p was more enriched in exosomes than in intracellular when Everolimus was employed.…”

“…1G), which indicated that Everolimus induced the secretion of miR-7-5p-loaded exosomes into the surrounding extracellular environment, resulting in the loss of miR-7-5p in intracellular. Furthermore, we performed siTSC1/2 to active [22] but Everolimus to inhibit the activity of mTORC1. After con rming the expression of mTOR, TSC1 and TSC2 following indicated treatments (Figure S1B), we found that miR-7-5p was more enriched in exosomes than in intracellular when Everolimus was employed.…”