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Published on: February 12, 2018
Smurf1: A possible therapeutic target in dry age-related macular degeneration
Duo Li1, Ting-Ting Wei2, Jiping Cai1
1Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, China; Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu Province, China.
Abstract:
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 (NaIO3) in C57BL/6J mice was the animal model of retina degeneration. In NaIO3 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.
Insights
Smad ubiquitylation regulatory factor-1 (Smurf1) exacerbates retinal oxidative stress and inflammation. Inhibiting Smurf1 alleviates retina degeneration, suggesting it as a therapeutic target for reactive oxygen species (ROS) injury.
Area of Science:
- Biochemistry
- Cell Biology
- Ophthalmology
Background:
- Smad ubiquitylation regulatory factor-1 (Smurf1) is an E3 ubiquitin ligase involved in the BMP pathway.
- The specific role of Smurf1 in retinal degeneration and oxidative stress remains largely unknown.
- Understanding Smurf1's function is crucial for developing new therapeutic strategies for retinal diseases.
Purpose of the Study:
- To investigate the role of Smurf1 in retina degeneration induced by oxidative stress.
- To explore the potential of Smurf1 as a therapeutic target for retinal oxidative injury.
Main Methods:
- Established a mouse model of retina degeneration using sodium iodate (NaIO3) and an oxidative stress model in ARPE-19 cells using tert-butyl hydroperoxide (TBH).
- Utilized a specific Smurf1 inhibitor (A01) administered via intravitreal injection and in cell culture.
- Employed lentivirus-mediated overexpression of Smurf1 and inhibition of beta-transducin repeat containing E3 ubiquitin protein ligase (β-TrCP) using GS143.
- Analyzed gene and protein expression, cell death, inflammation markers, and retinal structure.
Main Results:
- Smurf1 expression was upregulated in both in vivo and in vitro models of retinal injury.
- Inhibition of Smurf1 alleviated acute retinal injury, reduced cell death, and suppressed inflammation.
- Smurf1 promoted epithelial-mesenchymal transition (EMT) and upregulated key inflammatory mediators like NF-κB, NLRP3, and IL-1β.
- Smurf1's interaction with β-TrCP suggests a complex regulatory mechanism in the NF-κB pathway, where β-TrCP may act as a negative regulator.
Conclusions:
- Smurf1 plays a significant role in exacerbating oxidative stress and inflammation in the retina.
- Targeting Smurf1 offers a promising therapeutic approach for treating reactive oxygen species (ROS)-induced retinal degeneration.
- Further research into the Smurf1-β-TrCP interaction could reveal novel therapeutic targets.
