CLIC4, also known as chloride intracellular channel 4, is a multifunctional protein belonging to the chloride intracellular channel family. It is involved in diverse biological functions such as endosomal trafficking, endothelial barrier control, and regulation of the TGF-β signaling pathway. It has been implicated in various biological processes like cell growth, differentiation, and apoptosis, and is of great importance in understanding disease pathophysiology [1,2,5,7]. Genetic models, including KO/CKO mouse models, are valuable tools for studying CLIC4's function.

In pulmonary arterial hypertension, increased CLIC4 expression is linked to endothelial dysfunction. Proteomic analysis identified Arf6 as an effector of CLIC4, and its inhibition could restore BMPRII expression and attenuate the disease in Sugen/hypoxia mice and monocrotaline rats [1]. In endothelial cells, CLIC4 is crucial for PAR1-mediated signaling and RhoA-dependent endothelial barrier disruption, as shown by endothelial-specific Clic4 knockout in mice [2]. In gastric cancer, CLIC4 suppresses tumor growth by inhibiting cancer cell stemness and EMT, with its expression inversely correlated with the clinical stage [3]. In glioma, high CLIC4 expression is associated with greater malignancy and poor prognosis [4]. In skin, its levels are reduced in cancer cell lines, and overexpression in cancer cells inhibits tumor growth, while in tumor stromal cells it stimulates growth [5]. In cardiomyocytes, loss of CLIC4 in a murine model increased myocardial infarction and reduced cardiac function after IR injury [6]. In breast cancer, constitutive ablation of host Clic4 in murine models nearly eliminated lung metastases without reducing primary tumor weight, indicating its requirement for host metastatic competence [8].

In conclusion, CLIC4 is involved in a wide range of biological functions, including endosomal trafficking, endothelial function, and cancer-related processes. Gene knockout and conditional knockout mouse models have revealed its roles in diseases such as pulmonary hypertension, cancer, and cardiovascular diseases. These models have provided crucial insights into the molecular mechanisms underlying these diseases, highlighting CLIC4 as a potential therapeutic target.

References:

1. Abdul-Salam, Vahitha B, Russomanno, Giusy, Chien-Nien, Chen, Endruschat, Jens, Wojciak-Stothard, Beata. . CLIC4/Arf6 Pathway. In Circulation research, 124, 52-65. doi:10.1161/CIRCRESAHA.118.313705. https://pubmed.ncbi.nlm.nih.gov/30582444/

2. Kleinjan, Matthew L, Mao, De Yu, Naiche, L A, Mehta, Dolly, Kitajewski, Jan. 2023. CLIC4 Regulates Endothelial Barrier Control by Mediating PAR1 Signaling via RhoA. In Arteriosclerosis, thrombosis, and vascular biology, 43, 1441-1454. doi:10.1161/ATVBAHA.123.319206. https://pubmed.ncbi.nlm.nih.gov/37317855/

3. Wang, Baolong, Zheng, Jiqing, Chen, Qiongyuan, Song, Yao-Hua, Zhou, Jin. . CLIC4 abrogation promotes epithelial-mesenchymal transition in gastric cancer. In Carcinogenesis, 41, 841-849. doi:10.1093/carcin/bgz156. https://pubmed.ncbi.nlm.nih.gov/31560739/

4. Liu, Zhichun, Liu, Junhui, Chen, Zhibiao, Huang, Shulan, Xu, Haitao. 2024. CLIC4 Is a New Biomarker for Glioma Prognosis. In Biomedicines, 12, . doi:10.3390/biomedicines12112579. https://pubmed.ncbi.nlm.nih.gov/39595145/

5. Suh, Kwang S, Malik, Mariam, Shukla, Anjali, Yuspa, Stuart H. . CLIC4, skin homeostasis and cutaneous cancer: surprising connections. In Molecular carcinogenesis, 46, 599-604. doi:. https://pubmed.ncbi.nlm.nih.gov/17443730/

6. Ponnalagu, Devasena, Hamilton, Shanna, Sanghvi, Shridhar, Koch, Walter J, Singh, Harpreet. 2022. CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection. In Science advances, 8, eabo1244. doi:10.1126/sciadv.abo1244. https://pubmed.ncbi.nlm.nih.gov/36269835/

7. Shukla, Anjali, Yuspa, Stuart H. . CLIC4 and Schnurri-2: a dynamic duo in TGF-beta signaling with broader implications in cellular homeostasis and disease. In Nucleus (Austin, Tex.), 1, 144-9. doi:. https://pubmed.ncbi.nlm.nih.gov/20617112/

8. Sanchez, Vanesa C, Yang, Howard H, Craig-Lucas, Alayna, Hunter, Kent W, Yuspa, Stuart H. 2022. Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence. In PLoS genetics, 18, e1010271. doi:10.1371/journal.pgen.1010271. https://pubmed.ncbi.nlm.nih.gov/35727842/