Clca1, chloride channel accessory 1, belongs to the calcium-sensitive chloride conductance protein family [5]. It is a secreted protein with protease activity [2,3]. CLCA1 is mainly expressed in the colon, small intestine, appendix and is associated with multiple biological processes and diseases. It has been implicated in the regulation of ion secretion and mucus production in the airway [3], and may play a role in maintaining gastrointestinal homeostasis [4]. In addition, it is associated with inflammatory airway diseases and has potential links to chronic obstructive airway diseases, asthma and other respiratory diseases [1,2,3,6]. Genetic models, such as gene knockout mouse models, can be valuable for studying its functions.

In a study on airway mucus production, mice lacking Clca1 expression showed the same degree of mucous cell metaplasia and airway hyperreactivity as asthmatic wild-type mice. However, treatment with secreted N-Clca1 in vivo led to intraluminal mucus accumulation, and this mucus production in polarized human airway epithelial cells was dependent on TMEM16A expression, suggesting Clca1 may regulate airway mucus production through TMEM16A [3]. In ulcerative colitis, Rab7-dependent regulation of Clca1 was shown to be important for maintaining mucosal homeostasis. Lowered Rab7 expression in goblet cells led to increased Clca1 expression, compromised mucus layer and enhanced susceptibility to colitis [4]. In colorectal cancer, the expression level of Clca1 in cancer tissues was significantly decreased compared to adjacent normal tissue. Upregulated Clca1 suppressed CRC growth and metastasis in vitro and in vivo, and it may function as a tumor suppressor via inhibiting the Wnt/β-catenin signaling pathway and the EMT process [5]. In acute respiratory distress syndrome (ARDS), the level of Clca1 was significantly increased in patients and in a mouse model. Administration of Clca1 regulated ARDS phenotypes in mice, and it exacerbated the ARDS phenotypes through the p38 MAPK pathway [6].

In conclusion, Clca1 plays crucial roles in multiple biological processes. In the airway, it is involved in mucus production and ion secretion. In the gastrointestinal tract, it is related to mucosal homeostasis. In cancer, it may act as a tumor suppressor. The study of Clca1 using gene knockout or other genetic models has provided insights into its functions in diseases such as airway diseases, ulcerative colitis, and colorectal cancer, helping us better understand the underlying mechanisms and potentially guiding the development of new therapeutic strategies.

References:

1. Brett, Tom J. 2015. CLCA1 and TMEM16A: the link towards a potential cure for airway diseases. In Expert review of respiratory medicine, 9, 503-6. doi:10.1586/17476348.2015.1081064. https://pubmed.ncbi.nlm.nih.gov/26296094/

2. Xu, Yanan, Cao, Lili, Chen, Jiong, Ruan, Peisen, Ye, Qinsong. 2022. CLCA1 mediates the regulatory effect of IL-13 on pediatric asthma. In Frontiers in pediatrics, 10, 959439. doi:10.3389/fped.2022.959439. https://pubmed.ncbi.nlm.nih.gov/36313877/

3. Centeio, Raquel, Ousingsawat, Jiraporn, Schreiber, Rainer, Kunzelmann, Karl. 2021. CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A. In International journal of molecular sciences, 22, . doi:10.3390/ijms22105133. https://pubmed.ncbi.nlm.nih.gov/34066250/

4. Gaur, Preksha, Rajendran, Yesheswini, Srivastava, Bhagyashree, Ahuja, Vineet, Srikanth, Chittur. 2024. Rab7-dependent regulation of goblet cell protein CLCA1 modulates gastrointestinal homeostasis. In eLife, 12, . doi:10.7554/eLife.89776. https://pubmed.ncbi.nlm.nih.gov/38593125/

5. Li, Xiaofen, Hu, Wangxiong, Zhou, Jiaojiao, Yu, Jiekai, Zheng, Shu. 2017. CLCA1 suppresses colorectal cancer aggressiveness via inhibition of the Wnt/beta-catenin signaling pathway. In Cell communication and signaling : CCS, 15, 38. doi:10.1186/s12964-017-0192-z. https://pubmed.ncbi.nlm.nih.gov/28974231/

6. Lv, Xing, Zheng, Long, Zhang, Tianxiang, Guo, Xingxing, Song, Liqiang. 2024. CLCA1 exacerbates lung inflammation via p38 MAPK pathway in acute respiratory distress syndrome. In Experimental lung research, 50, 85-95. doi:10.1080/01902148.2024.2334262. https://pubmed.ncbi.nlm.nih.gov/38597420/