Cop1, also known as RFWD2, is an E3 ubiquitin ligase. It plays a vital role in multiple biological processes such as cell proliferation, apoptosis, DNA repair, and is involved in various signaling pathways. In plants, it is crucial for light signal transduction and photomorphogenic development, while in mammals, it has implications in tumorigenesis and stress response [2,4,5]. Genetic models, like gene knockout (KO) models, are valuable for studying its functions.

In triple-negative breast cancer (TNBC) syngeneic mouse models, deletion of Cop1 in cancer cells led to decreased secretion of macrophage-associated chemokines, reduced tumor macrophage infiltration, enhanced anti-tumor immunity, and strengthened immune checkpoint blockade (ICB) response. Mechanistically, Cop1 functions through proteasomal degradation of the C/ebpδ protein, with Trib2 acting as a scaffold [1]. In microglia, Cop1-deficient mouse models showed that loss of Cop1 led to rapid accumulation of c/EBPβ, driving a pro-inflammatory and neurodegeneration-related gene program, accelerating tau-mediated neurodegeneration [3].

In conclusion, Cop1 is essential in regulating multiple biological functions. Studies using KO mouse models have revealed its significant roles in cancer immunotherapy, as in TNBC, and in neurodegenerative diseases related to microglial inflammation. These findings contribute to understanding disease mechanisms and developing potential therapeutic strategies targeting Cop1.

References:

1. Wang, Xiaoqing, Tokheim, Collin, Gu, Shengqing Stan, Brown, Myles, Liu, X Shirley. 2021. In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target. In Cell, 184, 5357-5374.e22. doi:10.1016/j.cell.2021.09.006. https://pubmed.ncbi.nlm.nih.gov/34582788/

2. Xu, Dongqing. 2019. COP1 and BBXs-HY5-mediated light signal transduction in plants. In The New phytologist, 228, 1748-1753. doi:10.1111/nph.16296. https://pubmed.ncbi.nlm.nih.gov/31664720/

3. Ndoja, Ada, Reja, Rohit, Lee, Seung-Hye, Newton, Kim, Dixit, Vishva M. 2020. Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia. In Cell, 182, 1156-1169.e12. doi:10.1016/j.cell.2020.07.011. https://pubmed.ncbi.nlm.nih.gov/32795415/

4. Song, Yizuo, Liu, Yi, Pan, Shuya, Wang, Zhi-Wei, Zhu, Xueqiong. 2020. Role of the COP1 protein in cancer development and therapy. In Seminars in cancer biology, 67, 43-52. doi:10.1016/j.semcancer.2020.02.001. https://pubmed.ncbi.nlm.nih.gov/32027978/

5. Yi, Chunling, Deng, Xing Wang. 2005. COP1 - from plant photomorphogenesis to mammalian tumorigenesis. In Trends in cell biology, 15, 618-25. doi:. https://pubmed.ncbi.nlm.nih.gov/16198569/