Abhd16a, a member of the α/β hydrolase domain-containing (ABHD) protein family, has acylglycerol lipase and phosphatidylserine lipase activities. It encodes the major phosphatidylserine (PS) lipase in the brain, synthesizing lysophosphatidylserine, a crucial signaling lipid in the mammalian central nervous system. Its location in the main histocompatibility complex (MHC) III gene cluster implies a role in immunomodulation [1,2].

In KO mouse models, Abhd16a -/- mice show decreased brain lysophosphatidylserine levels, indicating its key role in lysophosphatidylserine biosynthesis [7]. In human studies, bi-allelic deleterious variants in ABHD16A in patients cause a complicated form of hereditary spastic paraplegia (HSP) associated with intellectual disability and cerebral anomalies [2,3,4]. Immunoblot analysis on fibroblasts from affected individuals demonstrated reduced ABHD16A protein levels. In gastric cancer, the non-classical miR-4646-5p, a product of Abhd16a intron 3, can regulate Abhd16a expression, leading to lysophosphatidylserine accumulation and promoting cancer metastasis [6]. Also, genetic deletion of Abhd16a expression in tumors enhanced the antitumor activity of type 1 innate lymphoid cells (ILC1s) as lysophosphatidylserine, whose synthesis is regulated by Abhd16a, inhibits ILC1 activation [5].

In conclusion, Abhd16a is essential for lysophosphatidylserine metabolism in the brain and has implications in immunomodulation. The study of Abhd16a using gene knockout models has revealed its significance in diseases such as hereditary spastic paraplegia and gastric cancer, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Xu, Jun, Gu, Weizhen, Ji, Kai, Zhu, Haihua, Zheng, Wenming. . Sequence analysis and structure prediction of ABHD16A and the roles of the ABHD family members in human disease. In Open biology, 8, . doi:10.1098/rsob.180017. https://pubmed.ncbi.nlm.nih.gov/29794032/

2. Lemire, Gabrielle, Ito, Yoko A, Marshall, Aren E, Bernard, Geneviève, Boycott, Kym M. 2021. ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies. In American journal of human genetics, 108, 2017-2023. doi:10.1016/j.ajhg.2021.09.005. https://pubmed.ncbi.nlm.nih.gov/34587489/

3. Miyake, Noriko, Silva, Sebastián, Troncoso, Mónica, Uchiyama, Yuri, Matsumoto, Naomichi. 2021. A homozygous ABHD16A variant causes a complex hereditary spastic paraplegia with developmental delay, absent speech, and characteristic face. In Clinical genetics, 101, 359-363. doi:10.1111/cge.14097. https://pubmed.ncbi.nlm.nih.gov/34866177/

4. Yahia, Ashraf, Elsayed, Liena E O, Valter, Remi, Lamari, Foudil, Stevanin, Giovanni. 2021. Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia. In Frontiers in neurology, 12, 720201. doi:10.3389/fneur.2021.720201. https://pubmed.ncbi.nlm.nih.gov/34489854/

5. Yan, Jiaxian, Zhang, Chi, Xu, Yueli, Jiang, Wei, Zhou, Rongbin. 2024. GPR34 is a metabolic immune checkpoint for ILC1-mediated antitumor immunity. In Nature immunology, 25, 2057-2067. doi:10.1038/s41590-024-01973-z. https://pubmed.ncbi.nlm.nih.gov/39358444/

6. Yang, Liping, Hou, Yixuan, Du, Yan-E, Wang, Rui, Liu, Manran. 2021. Mirtronic miR-4646-5p promotes gastric cancer metastasis by regulating ABHD16A and metabolite lysophosphatidylserines. In Cell death and differentiation, 28, 2708-2727. doi:10.1038/s41418-021-00779-y. https://pubmed.ncbi.nlm.nih.gov/33875796/

7. Kamat, Siddhesh S, Camara, Kaddy, Parsons, William H, Howell, Amy R, Cravatt, Benjamin F. 2015. Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay. In Nature chemical biology, 11, 164-71. doi:10.1038/nchembio.1721. https://pubmed.ncbi.nlm.nih.gov/25580854/