Ctsc, also known as cathepsin C, is a protease. It is responsible for the activation of neutrophil serine proteases, and is involved in pathways related to neutrophil function, such as neutrophil extracellular trap (NET) formation [1,5,6]. It has significance in multiple biological processes including those related to inflammation and immune response, and its study via genetic models can help understand its functions [1,5,6].

In breast cancer, Ctsc secreted by tumor cells promotes breast-to-lung metastasis. It activates neutrophil membrane-bound proteinase 3 (PR3), upregulates IL-6 and CCL3 for neutrophil recruitment, and induces NET formation which supports cancer cell growth in lungs. Targeting Ctsc with compound AZD7986 suppresses lung metastasis in mouse models [1]. In Papillon-Lefèvre syndrome, loss-of-function mutations in Ctsc lead to the disease, characterized by palmoplantar hyperkeratosis and periodontitis. Most mutations are missense, nonsense, or frameshift, mainly located in exons 5-7 [2]. In brain arteriovenous malformations (bAVMs), the CTSC-RAB38 fusion transcript is detected, associated with increased immune/inflammatory signaling and a higher hemorrhage rate [3]. In glioma, Ctsc is upregulated, promotes cell migration, invasion, and epithelial-mesenchymal transition (EMT) via activating the STAT3/SERPINA3 axis [4]. In lung ischemia-reperfusion injury, Ctsc from extracellular histone-induced M1 alveolar macrophages promotes NETosis through a NADPH oxidase-mediated pathway [5]. A rare Ctsc mutation in Papillon-Lefèvre syndrome abolishes serine protease activity and reduces NET formation but leaves other neutrophil functions normal [6].

In conclusion, Ctsc plays essential roles in neutrophil-related functions, and its dysregulation is associated with various diseases including cancer, Papillon-Lefèvre syndrome, and bAVMs. Studies using models like mouse models in breast cancer have revealed its role in disease-related biological processes, providing insights for potential therapeutic approaches [1,2,3,4,5,6].

References:

1. Xiao, Yansen, Cong, Min, Li, Jiatao, Yang, Qifeng, Hu, Guohong. 2021. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation. In Cancer cell, 39, 423-437.e7. doi:10.1016/j.ccell.2020.12.012. https://pubmed.ncbi.nlm.nih.gov/33450198/

2. Nagy, Nikoletta, Vályi, Péter, Csoma, Zsanett, Nagy, Katalin, Széll, Márta. 2014. CTSC and Papillon-Lefèvre syndrome: detection of recurrent mutations in Hungarian patients, a review of published variants and database update. In Molecular genetics & genomic medicine, 2, 217-28. doi:10.1002/mgg3.61. https://pubmed.ncbi.nlm.nih.gov/24936511/

3. Yan, Zihan, Fan, Guangming, Li, Hao, Cao, Yong, Zhao, Jizong. . The CTSC-RAB38 Fusion Transcript Is Associated With the Risk of Hemorrhage in Brain Arteriovenous Malformations. In Journal of neuropathology and experimental neurology, 80, 71-78. doi:10.1093/jnen/nlaa126. https://pubmed.ncbi.nlm.nih.gov/33120410/

4. Li, Qi, Wan, Chenguang, Zhang, Zhifei, Liu, Guangwei, Wang, Song. 2023. CTSC promoted the migration and invasion of glioma cells via activation of STAT3/SERPINA3 axis. In Gene, 893, 147948. doi:10.1016/j.gene.2023.147948. https://pubmed.ncbi.nlm.nih.gov/37925117/

5. Yu, Jing, Fu, Yu, Gao, Jiameng, Chen, Chang, Wen, Zongmei. 2024. Cathepsin C from extracellular histone-induced M1 alveolar macrophages promotes NETosis during lung ischemia-reperfusion injury. In Redox biology, 74, 103231. doi:10.1016/j.redox.2024.103231. https://pubmed.ncbi.nlm.nih.gov/38861835/

6. Sanchez Klose, Felix P, Björnsdottir, Halla, Dahlstrand Rudin, Agnes, Christenson, Karin, Bylund, Johan. 2021. A rare CTSC mutation in Papillon-Lefèvre Syndrome results in abolished serine protease activity and reduced NET formation but otherwise normal neutrophil function. In PloS one, 16, e0261724. doi:10.1371/journal.pone.0261724. https://pubmed.ncbi.nlm.nih.gov/34932608/