Senp8, also known as human deneddylase-1, is a SUMO peptidase family member and a key neuronal deneddylase. It specifically targets the NEDD8 protein, playing a crucial role in counteracting the neddylation process. Neddylation is a cellular process where NEDD8 is conjugated to target proteins, and Senp8's function in reversing this conjugation is important for various biological pathways, including those related to neuronal development, cell cycle progression, and the regulation of immune responses [1,5,6].

In neuronal development, Senp8 negatively regulates neurite outgrowth through multiple pathways like actin dynamics, Wnt/β -catenin signaling, and autophagic processes. Its absence leads to impaired excitatory synapse maturation, indicating its essential role in this process [1]. In acute lymphoblastic leukemia (ALL), VP -16 induces SENP8 accumulation, which confers a feedback drug resistance on ALL cells, and knockdown of SENP8 can sensitize these cells to VP -16 [4]. In colon cancer, SENP8 -mediated SHP2 deneddylation mediates tumor immunosuppression via the CD47/SIRPα axis [2]. In hepatitis B virus (HBV) propagation, overexpression of SENP8, which cleaves conjugated NEDD8, suppresses HBV propagation [3].

In summary, Senp8 is essential in regulating neddylation-related biological processes. Its study through gene-knockout or conditional-knockout models has revealed its significance in neurodevelopmental disorders, leukemia, colon cancer, and HBV-related diseases, providing potential therapeutic targets for these conditions.

References:

1. Song, Jae-Man, Kang, Minji, Lee, Seungha, Lee, Sanghyeon, Suh, Young Ho. 2023. Deneddylating enzyme SENP8 regulates neuronal development. In Journal of neurochemistry, 165, 348-361. doi:10.1111/jnc.15797. https://pubmed.ncbi.nlm.nih.gov/36847487/

2. Li, Yiqing, Zhou, Hui, Liu, Pan, Zhang, Xue, Ke, Yuehai. 2023. SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis. In The Journal of clinical investigation, 133, . doi:10.1172/JCI162870. https://pubmed.ncbi.nlm.nih.gov/36626230/

3. Chen, David Virya, Suzuki, Tatsuya, Itoh, Yumi, Matsuura, Yoshiharu, Okamoto, Toru. 2021. Deneddylation by SENP8 restricts hepatitis B virus propagation. In Microbiology and immunology, 65, 125-135. doi:10.1111/1348-0421.12874. https://pubmed.ncbi.nlm.nih.gov/33433029/

4. Sun, Shuzhang, Cheng, Yixuan, Hou, Wanxin, Li, Hegen, Xiao, Ning. 2024. Etoposide-induced SENP8 confers a feed-back drug resistance on acute lymphoblastic leukemia cells. In Biochemistry and biophysics reports, 37, 101650. doi:10.1016/j.bbrep.2024.101650. https://pubmed.ncbi.nlm.nih.gov/38314144/

5. Coleman, Kate E, Békés, Miklós, Chapman, Jessica R, Ueberheide, Beatrix M, Huang, Tony T. 2017. SENP8 limits aberrant neddylation of NEDD8 pathway components to promote cullin-RING ubiquitin ligase function. In eLife, 6, . doi:10.7554/eLife.24325. https://pubmed.ncbi.nlm.nih.gov/28475037/

6. Ehrentraut, Stefan F, Kominsky, Douglas J, Glover, Louise E, Bayless, Amanda J, Colgan, Sean P. 2012. Central role for endothelial human deneddylase-1/SENP8 in fine-tuning the vascular inflammatory response. In Journal of immunology (Baltimore, Md. : 1950), 190, 392-400. doi:10.4049/jimmunol.1202041. https://pubmed.ncbi.nlm.nih.gov/23209320/