查找使用阿拉丁产品的科研文献

Smurf1: A possible therapeutic target in dry age-related macular degeneration

Duo Li,Ting-Ting Wei,Jiping Cai,Tian-Hua Xie,Yong Yao,Lingpeng Zhu

Smad ubiquitylation regulatory factor-1 (Smurf1) is one of C2-WW-HECT domain E3 ubiquitin ligases , it can regulate BMP pathway by mediating ubiquitylation degradation of Smad1/Smad5. Many functions about Smurf1 also are still unknown, especially in retina . This research is about to explore the role of Smurf1 in retina degeneration . Tail vein injection of sodium iodate (NaIO 3 ) in C57BL/6J mice was the animal model of retina degeneration. In NaIO 3 model, Smurf1 had more expression than normal mice. Specific Smurf1 inhibitor, A01, was injected into vitreous cavity. Results showed that inhibiting Smurf1 could alleviate acute retina injury, such as keeping a better retina structure in living imaging and histologic sections, less cell death and inflammation activation. Tert-butyl hydroperoxide (TBH) was used to establish oxidative stress injury in human retinal pigments epithelial cell line (ARPE-19). Oxidative stress injury gradually caused co-upregulation of Smurf1, TGF-β1 and phosphorylated NF-κB (pNF-κB). TGF-β1 could directly induce Smurf1 expression. Inhibiting Smurf1 had an anti-epithelial mesenchymal transition (anti-EMT) function. Similarly, A01 also could inhibit the expression of pNF-κB, NLRP3 and IL-1β. At last, after searching bioinformatics database, Smurf1 had a possible interaction with beta-transducin repeat containing E3 ubiquitin protein ligase (β-TrCP), another E3 ubiquitin ligases. β-TrCP can mediate ubiquitination degradation of p-IκBα. Lentivirus- SMURF1 was used to overexpress Smurf1, and GS143 was used to inhibit β-TrCP. The results showed Smurf1 could directly induce NF-κB, pNF-κB, and NLRP3 expression, and keep a stable β-TrCP expression. However, inhibiting β-TrCP could cause more NF-κB activation and NLRP3 expression. Therefore, β-TrCP may play a negative role in NF-κB pathway activation. In summary, Smurf1 plays a role in exacerbating oxidative stress injury and inflammation in retina and may become a potential therapeutic target in ROS injury of retina.

SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB

Qin Xia,Xuan Liu,Lu Zhong,Jun Qu,Lei Dong

The calcium-activated phosphatase PPP3/calcineurin dephosphorylates TFEB (transcription factor EB) to trigger its nuclear translocation and the activation of macroautophagic/autophagic targets. However, the detailed molecular mechanism regulating TFEB activation remains poorly understood. Here, we highlighted the importance of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) in the activation of TFEB for lysosomal homeostasis. SMURF1 deficiency prevents the calcium-triggered ubiquitination of the catalytic subunit of PPP3/calcineurin in a manner consistent with defective autophagic degradation of damaged lysosomes. Mechanically, PPP3CB/CNA2 plays a bridging role in the recruitment of SMURF1 by LGALS3 (galectin 3) upon lysosome damage. Importantly, PPP3CB increases the dissociation of the N-terminal tail (NT) and C-terminal carbohydrate-recognition domain (CRD) of LGALS3, which may promote the formation of open conformers in a PPP3CB dephosphorylation activity-dependent manner. In addition, PPP3CB is ubiquitinated at lysine 146 by the recruited SMURF1 in response to intracellular calcium stimulation. The K63-linked ubiquitination of PPP3CB enhances the recruitment of TFEB. Moreover, TFEB directly interacts with both PPP3CB and the regulatory subunit PPP3R1 which facilitate the conformational correction of TFEB for its activation for the transcription of TFEB-targeted genes. Altogether, our results highlighted a critical mechanism for the regulation of PPP3/calcineurin activity via its ubiquitin ligase SMURF1 in response to lysosomal membrane damage, which may account for a potential target for the treatment of stress-related diseases.

SMURF1 inhibits the Th17 and Th17.1 polarization and improves the Treg/Th17 imbalance in systemic lupus erythematosus through the ubiquitination of RORγt

Wei Zhong,Leheng Feng,Wei Tian,Hongbo Qu,Haibo Xu,Ke Ning,Li Liu,Wei Liu,Xiaowei Gong,Hong Chen

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease . This study aimed to investigate the role of SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) in the Th17 and Th17.1 differentiation and Treg/Th17 imbalance, which are major factors contributing to the pathogenesis of SLE. SLE patients and healthy individuals were recruited to detect the SMURF1 levels in naïve CD4 + cells from peripheral blood. Purified and expanded naïve CD4 + T cells were employed to evaluate the effects of SMURF1 on Th17 and Th17.1 polarization in vitro. MRL/lpr lupus model was employed to explore the disease phenotype as well as Treg/Th17 balance in vivo. The results showed that SMURF1 was down-regulated in naïve CD4 + T cells in peripheral blood of patients with SLE and in spleen of MRL/lpr mice. SMURF1 overexpression suppressed the polarization of naïve CD4 + T cells toward Th17 and Th17.1 phenotype and down-regulated the expression of retinoid-related orphan receptor-gammat (RORγt). Subsequently, SMURF1 down-regulation aggravated the disease phenotype, inflammation, and the Treg/Th17 imbalance in MRL/lpr mice. Furthermore, we found that SMURF overexpression promoted the ubiquitination and decreases the stability of RORγt. In conclusion, SMURF1 inhibited the polarization of Th17 and Th17.1 cells and improved the Treg/Th17 imbalance in SLE, which was mediated as least partly by the ubiquitination of RORγt.

SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

Qin Xia,Hanfei Zheng,Yang Li,Wanting Xu,Chengwei Wu,Jiachen Xu,Shanhu Li,Lingqiang Zhang,Lei Dong