Ppt1, or palmitoyl protein thioesterase 1, is a lysosomal enzyme that catalyzes protein depalmitoylation. It plays a crucial role in regulating lysosomes, mitochondria, and lipid metabolism, and is involved in the occurrence and progression of diseases like neurological disorders and cancers [3]. Protein palmitoylation, a reversible lipid post-translational modification, is counteracted by Ppt1-mediated depalmitoylation, which impacts protein stability, membrane localization, and signal transduction [5].

In a Ppt1 -/- mouse model mimicking CLN1 disease, Ppt1-deficiency dysregulated lysosomal Ca++ homeostasis. Low levels of inositol 3-phosphate receptor-1 (IP3R1) due to reduced S-palmitoylated NFATC4 in the nucleus led to suppressed Ca++-dependent lysosomal enzyme activities, impaired autophagy, and lysosomal storage of undigested cargo [4]. In HCC, Ppt1 is mainly expressed in macrophages and promotes their immunosuppressive transformation. Pharmacological inhibition of Ppt1 enhanced the therapeutic efficacy of anti-PD-1 antibody in the HCC mouse model [1]. In melanoma mouse models, inhibiting Ppt1 enhanced the antitumor efficacy of anti-PD-1 antibody, associated with M2 to M1 macrophage phenotype switching and reduced myeloid-derived suppressor cells [6]. Also, in an Oxygen-Induced Retinopathy (OIR) mouse model, Ppt1-deficient mice showed attenuated angiogenesis compared to wild-type mice [2].

In summary, Ppt1 is essential for regulating cellular homeostasis, especially in terms of lysosomal function, lipid metabolism, and Ca++ homeostasis. Studies using Ppt1 KO mouse models have revealed its role in various disease conditions such as CLN1 disease, HCC, melanoma, and angiogenesis-related diseases, providing insights into potential therapeutic strategies targeting Ppt1 for these diseases.

References:

1. Weng, Jialei, Liu, Shaoqing, Zhou, Qiang, Zhou, Chenhao, Ren, Ning. . Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2022-006655. https://pubmed.ncbi.nlm.nih.gov/37385725/

2. Ma, Yidan, Yuan, Xinxin, Wei, Aodong, Zhu, Jiangli, Kong, Eryan. 2024. Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1. In Redox biology, 77, 103376. doi:10.1016/j.redox.2024.103376. https://pubmed.ncbi.nlm.nih.gov/39423458/

3. Zhou, Xin-Yi, Chang, Dong, Xu, Huang-Ying, Yin, Qiu-Yuan, Sun, Jian-Wei. . Progress on lysosomal PPT1-mediated regulation of cellular homeostasis and pathogenesis. In Yi chuan = Hereditas, 45, 874-886. doi:10.16288/j.yczz.23-186. https://pubmed.ncbi.nlm.nih.gov/37872111/

4. Mondal, Avisek, Appu, Abhilash P, Sadhukhan, Tamal, Liu, Aiyi, Mukherjee, Anil B. 2022. Ppt1-deficiency dysregulates lysosomal Ca++ homeostasis contributing to pathogenesis in a mouse model of CLN1 disease. In Journal of inherited metabolic disease, 45, 635-656. doi:10.1002/jimd.12485. https://pubmed.ncbi.nlm.nih.gov/35150145/

5. 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/

6. Sharma, Gaurav, Ojha, Rani, Noguera-Ortega, Estela, Gabrilovich, Dmitry I, Amaravadi, Ravi K. 2020. PPT1 inhibition enhances the antitumor activity of anti-PD-1 antibody in melanoma. In JCI insight, 5, . doi:10.1172/jci.insight.133225. https://pubmed.ncbi.nlm.nih.gov/32780726/