BRCC3, also known as BRCA1-BRCA2-containing complex subunit 3, is a JAMM domain-containing Zn2+ metalloprotease deubiquitinating enzyme. It modifies the activity and stability of substrate proteins through K63-dependent deubiquitination, and is implicated in pathways like BMP/TGF-β, NLRP3 and NLRP6 inflammasome activation, NF-κB signaling, and Hippo signaling, thus being important in maintaining physiological functions and disease development [1-10].

In pulmonary hypertension, BRCC3-deficient (Brcc3-/-) mice showed increased susceptibility due to inhibition of the ALK2-Smad1/5 signaling, while SM22α-BRCC3-Tg mice had ameliorated pulmonary hypertension as the ALK2-Smad1/5-PPARγ axis in pulmonary artery smooth muscle cells was activated. This indicates BRCC3's role in sustaining pulmonary vascular homeostasis by balancing BMP and TGF-β signaling [1]. In Tet2 clonal hematopoiesis-induced atherosclerosis, holomycin, a BRCC3 deubiquitinase inhibitor, reversed accelerated atherosclerosis in Tet2 CH mice, suggesting BRCC3-mediated NLRP3 deubiquitylation promotes inflammasome activation and atherosclerosis [2]. In colitis, CD82 deficiency decreased colitis severity in mice by increasing NLRP3 deubiquitination by BRCC3 [3].

In conclusion, BRCC3 is crucial in various biological processes and disease conditions. Gene-knockout mouse models have revealed its role in pulmonary hypertension, atherosclerosis, and colitis. Understanding BRCC3's functions helps in elucidating disease mechanisms and may offer potential therapeutic targets for these diseases.

References:

1. Shen, Hui, Gao, Ya, Ge, Dedong, Shyy, John Y-J, Gong, Kaizheng. 2024. BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension. In Circulation, 150, 132-150. doi:10.1161/CIRCULATIONAHA.123.066430. https://pubmed.ncbi.nlm.nih.gov/38557054/

2. Yalcinkaya, Mustafa, Liu, Wenli, Thomas, Leigh-Anne, Tabas, Ira, Tall, Alan R. 2023. BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis. In Circulation, 148, 1764-1777. doi:10.1161/CIRCULATIONAHA.123.065344. https://pubmed.ncbi.nlm.nih.gov/37781816/

3. Kim, Jae-Sung, Kim, Hyo Keun, Lee, Joongho, Yoon, Seokhyun, Yang, Chul-Su. 2023. Inhibition of CD82 improves colitis by increasing NLRP3 deubiquitination by BRCC3. In Cellular & molecular immunology, 20, 189-200. doi:10.1038/s41423-022-00971-1. https://pubmed.ncbi.nlm.nih.gov/36600050/