Nedd8-KO Mouse

Nedd8, a ubiquitin-like protein, plays a crucial role in the regulation of diverse biological processes. It is tightly associated with the cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation pathway. Neddylation, the process of attaching Nedd8 to target proteins, is essential for the proper functioning of CRLs, which are involved in many cellular processes such as cell cycle regulation, DNA repair, and signal transduction [1,3].

In triple-negative breast cancer (TNBC), loss-of-function studies using CRISPR/Cas9 screens revealed that deletion of NEDD8 in cancer cells initially delays cell division, but cell proliferation recovers. However, it causes vulnerability to nivolumab (anti-PD-1), indicating NEDD8 as a potential synergistic drug target for PD-1/L1 blockade therapy. This shows how NEDD8 is conditionally essential in TNBC [2].

In conclusion, Nedd8 is vital for the regulation of CRL-mediated protein ubiquitylation, influencing numerous cellular processes. The discovery of its role in conferring vulnerability to immune checkpoint blockade in TNBC through loss-of-function models highlights its potential as a therapeutic target in this disease area.

References:

1. Baek, Kheewoong, Krist, David T, Prabu, J Rajan, Kleiger, Gary, Schulman, Brenda A. 2020. NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. In Nature, 578, 461-466. doi:10.1038/s41586-020-2000-y. https://pubmed.ncbi.nlm.nih.gov/32051583/

2. Papakyriacou, Irineos, Kutkaite, Ginte, Rúbies Bedós, Marta, Menden, Michael P, Mao, Yumeng. 2024. Loss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer. In Nature communications, 15, 3581. doi:10.1038/s41467-024-47987-x. https://pubmed.ncbi.nlm.nih.gov/38678024/

3. Schwechheimer, Claus. 2018. NEDD8-its role in the regulation of Cullin-RING ligases. In Current opinion in plant biology, 45, 112-119. doi:10.1016/j.pbi.2018.05.017. https://pubmed.ncbi.nlm.nih.gov/29909289/