Abhd17a-KO Mouse

Abhd17a, or alpha/beta hydrolase domain-containing protein 17A, functions as a depalmitoylating enzyme. Protein palmitoylation, a reversible lipid post-translational modification, is crucial for many biological processes such as protein-protein interaction, membrane localization, and signal transduction. Abhd17a is involved in reversing this modification, thus influencing various cellular functions and biological pathways [2].

In the context of NLRP3 inflammasome activation, Abhd17a depalmitoylates NLRP3. A human-heritable disease-associated mutation in NLRP3 was found to be associated with defective Abhd17a binding and hyper-palmitoylation. Silencing of Abhd17a's homolog ZDHHC5 blocks NLRP3 oligomerization, NLRP3-NEK7 interaction, and formation of large intracellular ASC aggregates, leading to abrogation of caspase-1 activation, IL-1β/18 release, and GSDMD cleavage, both in human cells and in mice, suggesting its role in innate immune response [1]. In colorectal cancer, Abhd17a is identified as the depalmitoylating enzyme for Rap2b, altering its plasma membrane localization and inhibiting cell migration and invasion. PI3K phosphorylates Abhd17a to modulate its activity, highlighting its potential as a target for metastatic CRC treatment [3].

In conclusion, Abhd17a plays a vital role in regulating protein palmitoylation, thereby influencing multiple biological processes. Its function in depalmitoylating key proteins like NLRP3 and Rap2b reveals its significance in innate immunity and cancer metastasis. Studies using gene-silencing or potential knockout models in these contexts have provided insights into its role, suggesting it could be a potential target for treating NLRP3 inflammasome-driven diseases and metastatic colorectal cancer.

References:

1. Zheng, Sihao, Que, Xiangyong, Wang, Shuxian, Zhang, Pingfeng, Pei, Huadong. 2023. ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation. In Molecular cell, 83, 4570-4585.e7. doi:10.1016/j.molcel.2023.11.015. https://pubmed.ncbi.nlm.nih.gov/38092000/

2. Zhou, Binhui, Hao, Qianyun, Liang, Yinming, Kong, Eryan. 2022. Protein palmitoylation in cancer: molecular functions and therapeutic potential. In Molecular oncology, 17, 3-26. doi:10.1002/1878-0261.13308. https://pubmed.ncbi.nlm.nih.gov/36018061/

3. Zhu, Jiangli, Cao, Xize, Chen, Zhenshuai, Kang, Xiaohong, Kong, Eryan. 2024. Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer. In Cell death & disease, 15, 675. doi:10.1038/s41419-024-07061-2. https://pubmed.ncbi.nlm.nih.gov/39277583/