Lypla1, also known as acyl protein thioesterase 1 (APT1), is an enzyme that catalyzes protein depalmitoylation, the removal of thioester-linked long-chain fatty acids from cysteine residues in proteins. This process is crucial for balancing the palmitoylation cycle, which is involved in efficient membrane targeting, signaling, growth, and cell organization [2].

In the context of hypoxia-induced mitophagy in triple-negative breast cancer (TNBC), LYPLA1 depalmitoylates GPCPD1, a key enzyme in choline metabolism. This depalmitoylation facilitates GPCPD1's relocation to the outer mitochondrial membrane, where it binds to VDAC1, interfering with its oligomerization. The increased monomer of VDAC1 recruits PRKN-mediated polyubiquitination, triggering mitophagy. GPCPD1-mediated mitophagy promotes tumor growth and metastasis in TNBC [1]. In the case of porcine reproductive and respiratory syndrome virus (PRRSV-2) replication, LYPLA1 de-palmitoylates the N protein of PRRSV-2, counteracting the activity of ZDHHC3 (a palmitoyl transferase) on PRRSV replication. Administration of a small-molecule inhibitor targeting LYPLA1 could hinder PRRSV-2 replication [3]. Additionally, LYPLA1 can reverse the S-acylation of SQSTM1/p62 (catalyzed by ZDHHC19), and S-acylation of SQSTM1 enhances its affinity with the phagophore membrane, promoting efficient autophagic degradation of ubiquitinated substrates [4].

In summary, Lypla1 plays essential roles in processes such as mitophagy, virus replication, and selective autophagy through its protein depalmitoylation function. Studies related to Lypla1, especially those using loss-of-function models like inhibitor-based approaches, have revealed its significance in diseases like TNBC and in virus-host interactions, providing potential therapeutic targets for these conditions.

References:

1. Liu, Ying, Zhang, Hanwen, Liu, Yiwei, Zhang, Ning, Yang, Qifeng. 2023. Hypoxia-induced GPCPD1 depalmitoylation triggers mitophagy via regulating PRKN-mediated ubiquitination of VDAC1. In Autophagy, 19, 2443-2463. doi:10.1080/15548627.2023.2182482. https://pubmed.ncbi.nlm.nih.gov/36803235/

2. Won, Sang Joon, Cheung See Kit, Melanie, Martin, Brent R. 2017. Protein depalmitoylases. In Critical reviews in biochemistry and molecular biology, 53, 83-98. doi:10.1080/10409238.2017.1409191. https://pubmed.ncbi.nlm.nih.gov/29239216/

3. Jing, Huiyuan, Liu, Ying, Song, Yvzhen, Liu, Jie, Zhao, Pandeng. 2025. ZDHHC3-LYPLA1 regulates PRRSV-2 replication through reversible palmitoylation. In Veterinary microbiology, 301, 110368. doi:10.1016/j.vetmic.2025.110368. https://pubmed.ncbi.nlm.nih.gov/39787744/

4. Huang, Xue, Liu, Lu, Yao, Jia, Xiang, Tingxiu, Yang, Aimin. 2024. S-acylation regulates SQSTM1/p62-mediated selective autophagy. In Autophagy, 20, 1467-1469. doi:10.1080/15548627.2023.2297623. https://pubmed.ncbi.nlm.nih.gov/38124295/