Btrc, also known as beta-transducin repeat containing E3 ubiquitin protein ligase, is an E3 ubiquitin ligase. It plays a crucial role in the ubiquitination and proteasomal degradation of target proteins, thereby regulating various cellular processes. It is involved in multiple pathways, such as the NF-κB pathway by targeting IκBα for degradation, and is important for maintaining normal cellular functions and homeostasis [4].

In a Chinese family with split hand/foot malformation type 3, a 120 kb microduplication containing only Btrc was identified. The transcription levels of Btrc mRNA in the proband's lymphocyte were significantly higher than in healthy controls, suggesting that abnormal Btrc expression may cause limb malformation [1]. In breast cancer, phosphorylation of ULK1 by MAPK1/3 kinase triggers its interaction with Btrc and subsequent degradation, attenuating mitophagy and promoting bone metastasis [2]. In hepatic steatosis models, Btrc was upregulated, negatively correlated with decreased ATGL levels, and identified as the E3 ligase for ATGL. Knockdown of Btrc ameliorated steatosis [3]. In triple-negative breast cancer, WBP2 promotes Btrc mRNA stability, enhancing cell migration and invasion via NF-κB activation [4]. In osteosarcoma, lnc-SELPLG-2:1 activates oncogenesis through the hsa-miR-10a-5p/Btrc cascade [5]. In colorectal cancer, miR-224 targets Btrc, promoting cell migration and invasion [6]. Exosomal GPT2 from triple-negative breast cancer cells activates Btrc to promote metastasis [7]. Btrc also mediates the degradation of human Lipin-1 [8]. In cardiac senescence, circHIPK3 acts as a scaffold to recruit Btrc to degrade HuR, preventing cardiac senescence [9].

In summary, Btrc, as an E3 ubiquitin ligase, is involved in a wide range of biological processes, including limb development, cancer metastasis, hepatic steatosis, and cardiac senescence. Studies on Btrc using various genetic models, such as the identification of microduplications in human families and functional studies in cells, have provided insights into its role in these disease conditions, highlighting its potential as a therapeutic target.

References:

1. Qiu, Liyan, Li, Caimin, Zheng, Guiyun, Yang, Tuyin, Yang, Fang. 2022. Microduplication of BTRC detected in a Chinese family with split hand/foot malformation type 3. In Clinical genetics, 102, 451-456. doi:10.1111/cge.14204. https://pubmed.ncbi.nlm.nih.gov/35908152/

2. Deng, Rong, Zhang, Hai-Liang, Huang, Jun-Hao, Tang, Jun, Zhu, Xiao-Feng. 2020. MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis. In Autophagy, 17, 3011-3029. doi:10.1080/15548627.2020.1850609. https://pubmed.ncbi.nlm.nih.gov/33213267/

3. Qi, Weiwei, Fang, Zhenzhen, Luo, Chuanghua, Yang, Xia, Gao, Guoquan. . The critical role of BTRC in hepatic steatosis as an ATGL E3 ligase. In Journal of molecular cell biology, 15, . doi:10.1093/jmcb/mjad064. https://pubmed.ncbi.nlm.nih.gov/37873692/

4. Lim, Yvonne Xinyi, Lin, Hexian, Chu, Tinghine, Lim, Yoon Pin. 2021. WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple-negative breast cancer via NF-κB activation. In Molecular oncology, 16, 422-446. doi:10.1002/1878-0261.13048. https://pubmed.ncbi.nlm.nih.gov/34197030/

5. Li, Shiyuan, Zeng, Ming, Yang, Lin, Kuang, Manyuan, Li, Jiaying. 2022. Lnc-SELPLG-2:1 enhanced osteosarcoma oncogenesis via hsa-miR-10a-5p and the BTRC cascade. In BMC cancer, 22, 1044. doi:10.1186/s12885-022-10040-5. https://pubmed.ncbi.nlm.nih.gov/36199080/

6. Zheng, Qi, Yu, Jane J, Li, Chenggang, Wang, Jiping, Wang, Shuyang. 2020. miR-224 targets BTRC and promotes cell migration and invasion in colorectal cancer. In 3 Biotech, 10, 485. doi:10.1007/s13205-020-02477-x. https://pubmed.ncbi.nlm.nih.gov/33117626/

7. Cui, Mingqing, Peng, Jiawei, Zhou, Yuanyuan, Wang, Xixi, Cui, Daxiang. 2023. Exosomal GPT2 derived from triple-negative breast cancer cells promotes metastasis by activating BTRC. In Thoracic cancer, 14, 2018-2025. doi:10.1111/1759-7714.14984. https://pubmed.ncbi.nlm.nih.gov/37287397/

8. Ishimoto, Kenji, Hayase, Ayaka, Kumagai, Fumiko, Tachibana, Keisuke, Doi, Takefumi. 2017. Degradation of human Lipin-1 by BTRC E3 ubiquitin ligase. In Biochemical and biophysical research communications, 488, 159-164. doi:10.1016/j.bbrc.2017.04.159. https://pubmed.ncbi.nlm.nih.gov/28483528/

9. Ding, Fengzhi, Lu, Lin, Wu, Chengjie, Yu, Xi-Yong, Li, Yangxin. 2022. circHIPK3 prevents cardiac senescence by acting as a scaffold to recruit ubiquitin ligase to degrade HuR. In Theranostics, 12, 7550-7566. doi:10.7150/thno.77630. https://pubmed.ncbi.nlm.nih.gov/36438474/