Senp8-KO Mouse

Senp8, also known as human deneddylase-1, is a SUMO peptidase family member that specifically acts as a deneddylating enzyme. Neddylation is a cellular process where NEDD8 is conjugated to target proteins, and Senp8 counteracts this by removing NEDD8 from over-neddylated proteins. It is involved in multiple pathways such as actin dynamics, Wnt/β-catenin signaling, and autophagic processes, and plays a crucial role in maintaining proper neddylation levels for cullin-RING ubiquitin ligase (CRL)-dependent proteostasis [5,6].

In neuronal development, Senp8 negatively regulates neurite outgrowth, which subsequently impairs excitatory synapse maturation. Its expression levels are developmentally regulated, peaking around the first postnatal week and then diminishing in mature brain and neurons [1]. In hepatitis B virus (HBV) propagation, overexpression of Senp8, which cleaves conjugated NEDD8, suppresses HBV propagation, indicating that neddylation plays an important role in the late stages of HBV life cycles [2]. In colon cancer, Senp8-mediated SHP2 deneddylation via the CD47/SIRPα axis mediates tumor immunosuppression [3]. In acute lymphoblastic leukemia (ALL), SENP8 is highly expressed in relapsed specimens, and overexpressing SENP8 reduces the chemosensitivity of ALL cells to etoposide, while knockdown of SENP8 can sensitize cells to the drug [4].

In conclusion, Senp8 is a key deneddylating enzyme with essential functions in neuronal development, viral propagation, tumor immunosuppression, and drug resistance in leukemia. Studies on Senp8, especially through loss-of-function experiments in relevant models, have provided insights into its role in these biological processes and disease conditions, potentially offering new therapeutic targets for neurodevelopmental disorders, HBV-related diseases, and certain cancers.