Ufd1, short for ubiquitin fusion degradation 1, is a crucial component in the ubiquitin-proteasome pathway. It functions as a co-factor in the Cdc48-Ufd1-Npl4 complex, which is involved in recognizing polyubiquitin-tagged proteins and facilitating their presentation to the 26S proteasome for degradation [1]. This pathway is essential for maintaining cellular protein homeostasis, and Ufd1's role within it is vital for eukaryotic cellular processes [2].

In zebrafish, allelic loss of ufd1 induces tumor cell apoptosis and impairs MYC-driven T-cell acute lymphoblastic leukemia (T-ALL) progression without affecting general health. Ufd1 inactivation in human T-ALL cells impairs endoplasmic reticulum-associated degradation (ERAD), exacerbates ER stress, and induces apoptosis. It also promotes the proapoptotic unfolded protein response (UPR) mediated by protein kinase RNA-like ER kinase (PERK), indicating its importance in the ER stress response and MYC-mediated leukemia aggressiveness [4]. In Enterovirus A71 (EVA71) infection, knockdown of UFD1 significantly decreased the binding and entry of EVA71 to host cells through modulating the levels of nucleolin protein, a coreceptor of EVA71, revealing its role in viral entry [3].

In conclusion, Ufd1 is essential for the ubiquitin-proteasome pathway, playing key roles in maintaining protein homeostasis. Model-based research, such as the zebrafish ufd1 allelic loss study, has revealed its significance in cancer, specifically in MYC-driven T-ALL, and in viral entry, like that of EVA71. These findings provide insights into potential therapeutic targets for related diseases.

References:

1. Bays, Nathan W, Hampton, Randolph Y. . Cdc48-Ufd1-Npl4: stuck in the middle with Ub. In Current biology : CB, 12, R366-71. doi:. https://pubmed.ncbi.nlm.nih.gov/12015140/

2. Lee, Hyein G, Lemmon, Abigail A, Lima, Christopher D. 2022. SUMO enhances unfolding of SUMO-polyubiquitin-modified substrates by the Ufd1/Npl4/Cdc48 complex. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2213703120. doi:10.1073/pnas.2213703120. https://pubmed.ncbi.nlm.nih.gov/36574706/

3. Yan, Jingjing, Wang, Meng, Wang, Min, Yi, Zhigang, Zhang, Shuye. 2020. Involvement of VCP/UFD1/Nucleolin in the viral entry of Enterovirus A species. In Virus research, 283, 197974. doi:10.1016/j.virusres.2020.197974. https://pubmed.ncbi.nlm.nih.gov/32289342/

4. Huiting, L N, Samaha, Y, Zhang, G L, Kelliher, M A, Feng, H. 2018. UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response. In Leukemia, 32, 2339-2351. doi:10.1038/s41375-018-0141-x. https://pubmed.ncbi.nlm.nih.gov/29743725/