Smurf1, short for SMAD specific E3 ubiquitin protein ligase 1, is a HECT-type E3 ubiquitin ligase. It is involved in multiple biological pathways, such as the bone morphogenetic protein pathway, non-canonical Wnt pathway, and mitogen-activated protein kinase pathway. Smurf1 plays crucial roles in cell growth, morphogenesis, migration, polarity, and autophagy, and is related to physiological manifestations like age-dependent bone formation deficiency and tumor cell invasion [8]. Gene knockout (KO) and conditional knockout (CKO) mouse models have been valuable for studying its functions.

In cancer, Smurf1 overexpression is linked to poor prognosis in various cancers. For example, in glioblastoma, colon cancer, and clear cell renal cell carcinoma, it acts as a tumor promoter by ubiquitinating and degrading tumor-suppressing proteins. In KRAS-mutated colorectal cancer, Smurf1-mediated PDK1 neddylation activates the PI3K-Akt signaling pathway and promotes tumorigenesis, and Smurf1 deficiency reduces tumor formation in a genetic mouse model [1,4]. In autophagy, Smurf1 controls TFEB nuclear import for lysosomal biogenesis. Blocking Smurf1 prevents TFEB nuclear translocation in response to lysosomal damage [2]. In hepatocellular carcinoma, Smurf1-mediated UVRAG ubiquitination promotes autophagosome maturation and inhibits tumor growth [3]. In glioblastoma, Smurf1 protects against endoplasmic reticulum stress by degrading KEAP1 to activate the NRF2 antioxidant pathway, and its knockdown reduces cell proliferation and growth in xenografts [5]. In lupus nephritis, Smurf1 upregulation activates the cGAS/STING/IFN-1 signal axis by ubiquitinating YY1, accelerating disease progression, and Smurf1 knockdown inhibits LN progression in vivo [7]. In ameloblasts, Smurf1 regulates polarization through ubiquitination-mediated degradation of RhoA, and local knockdown in rat lower incisor ameloblasts leads to polarity loss and enamel disorders [6]. In dry age-related macular degeneration, inhibiting Smurf1 in a mouse model alleviates acute retina injury, and in an in vitro oxidative stress model, it has an anti-epithelial mesenchymal transition function [9].

In summary, Smurf1 is a key E3 ubiquitin ligase involved in numerous biological functions, especially in processes related to cancer, autophagy, and cell polarity. Studies using KO/CKO mouse models have significantly enhanced our understanding of its role in these disease areas, providing potential therapeutic targets for various diseases such as cancer, lupus nephritis, and age-related macular degeneration.

References:

1. Xia, Qin, Li, Yang, Han, Da, Dong, Lei. 2020. SMURF1, a promoter of tumor cell progression? In Cancer gene therapy, 28, 551-565. doi:10.1038/s41417-020-00255-8. https://pubmed.ncbi.nlm.nih.gov/33204002/

2. Xia, Qin, Zheng, Hanfei, Li, Yang, Zhang, Lingqiang, Dong, Lei. 2023. SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis. In Autophagy, 20, 735-751. doi:10.1080/15548627.2023.2267413. https://pubmed.ncbi.nlm.nih.gov/37909662/

3. Feng, Xing, Jia, Yanyan, Zhang, Yuyu, Qiu, Xingfeng, Zhang, Zhiyong. 2019. Ubiquitination of UVRAG by SMURF1 promotes autophagosome maturation and inhibits hepatocellular carcinoma growth. In Autophagy, 15, 1130-1149. doi:10.1080/15548627.2019.1570063. https://pubmed.ncbi.nlm.nih.gov/30686098/

4. Peng, Zhiqiang, Fang, Wei, Wu, Bo, Cui, Chun-Ping, Zhang, Lingqiang. 2024. Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer. In Nature chemical biology, 21, 59-70. doi:10.1038/s41589-024-01683-5. https://pubmed.ncbi.nlm.nih.gov/39039255/

5. Dong, Lei, Xu, Mengchuan, Li, Yang, Zhou, Liying, Xia, Qin. 2023. SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway. In Cell death & disease, 14, 361. doi:10.1038/s41419-023-05873-2. https://pubmed.ncbi.nlm.nih.gov/37316499/

6. Niu, Haoman, Bi, Fei, Zhao, Wenjun, Guo, Weihua, Chen, Yu. 2022. Smurf1 regulates ameloblast polarization by ubiquitination-mediated degradation of RhoA. In Cell proliferation, 56, e13387. doi:10.1111/cpr.13387. https://pubmed.ncbi.nlm.nih.gov/36579844/

7. Li, Xiaoyan, Tao, Sisi, Xu, Zhiquan, Xiang, Wei, He, Xiaojie. 2023. SMURF1 activates the cGAS/STING/IFN-1 signal axis by mediating YY1 ubiquitination to accelerate the progression of lupus nephritis. In Autoimmunity, 56, 2281235. doi:10.1080/08916934.2023.2281235. https://pubmed.ncbi.nlm.nih.gov/37994046/

8. Cao, Yu, Zhang, Lingqiang. 2012. A Smurf1 tale: function and regulation of an ubiquitin ligase in multiple cellular networks. In Cellular and molecular life sciences : CMLS, 70, 2305-17. doi:10.1007/s00018-012-1170-7. https://pubmed.ncbi.nlm.nih.gov/23007848/

9. Li, Duo, Wei, Ting-Ting, Cai, Jiping, Yao, Yong, Zhu, Lingpeng. 2023. Smurf1: A possible therapeutic target in dry age-related macular degeneration. In Experimental eye research, 233, 109549. doi:10.1016/j.exer.2023.109549. https://pubmed.ncbi.nlm.nih.gov/37348673/