Abraxas2, also known as KIAA0157 and FAM175B, is a scaffolding protein within the BRCC3 isopeptidase complex (BRISC). BRISC is a K63-specific deubiquitinase complex crucial for cellular signaling pathways, such as inflammation and the regulation of Janus kinase 2 (JAK2) signaling [1,2]. Abraxas2 is essential for BRCC36 enzymatic activity in BRISC, which has implications in DNA repair and immune regulation [5].

In a study, Kiaa0157 deficiency in mice led to an expansion of phenotypic and functional hematopoietic stem cells (HSCs). This indicates that Abraxas2, through BRISC, limits HSC expansion by regulating JAK2 K63-ubiquitination [2]. Additionally, in human endometrium of polycystic ovary syndrome (PCOS) patients, Lasso regression analysis found that Abraxas2 was associated with miscarriage in PCOS patients [3]. Also, in esophageal squamous cell carcinoma, FAM175B (Abraxas2) inhibited ATF4 ubiquitination and promoted cell apoptosis in a p53-independent manner, and its expression loss may be an early diagnostic biomarker [4].

In summary, Abraxas2 is vital for the function of the BRISC complex, playing a role in multiple biological processes. Findings from gene-knockout (KO) mouse models and other functional studies have revealed its significance in hematopoietic stem cell regulation, PCOS-related miscarriage, and esophageal squamous cell carcinoma. These studies provide insights into the biological functions of Abraxas2 and its potential implications in related disease areas.

References:

1. Pan, Xinming, Sun, Yangyang, Liu, Jianan, Yao, Huochun, Ma, Jiale. 2025. A bacterial RING ubiquitin ligase triggering stepwise degradation of BRISC via TOLLIP-mediated selective autophagy manipulates host inflammatory response. In Autophagy, , 1-20. doi:10.1080/15548627.2025.2468140. https://pubmed.ncbi.nlm.nih.gov/40013521/

2. Donaghy, Ryan, Han, Xu, Rozenova, Krasimira, Greenberg, Roger A, Tong, Wei. 2019. The BRISC deubiquitinating enzyme complex limits hematopoietic stem cell expansion by regulating JAK2 K63-ubiquitination. In Blood, 133, 1560-1571. doi:10.1182/blood-2018-10-877563. https://pubmed.ncbi.nlm.nih.gov/30755420/

3. Yang, Xin, Xiaoping, Wang, Nan, Ding, Zhao, Mengni, Wang, Fang. 2023. Proteomic and bioinformatic analysis of human endometrium from polycystic ovarian syndrome with and without insulin resistance. In Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 39, 2173948. doi:10.1080/09513590.2023.2173948. https://pubmed.ncbi.nlm.nih.gov/36750132/

4. Zhao, Yu, Yu, Yang, Li, Hengcun, Min, Li, Zhang, Shutian. 2019. FAM175B promotes apoptosis by inhibiting ATF4 ubiquitination in esophageal squamous cell carcinoma. In Molecular oncology, 13, 1150-1165. doi:10.1002/1878-0261.12474. https://pubmed.ncbi.nlm.nih.gov/30854784/

5. Zeqiraj, Elton, Tian, Lei, Piggott, Christopher A, Greenberg, Roger A, Sicheri, Frank. 2015. Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function. In Molecular cell, 59, 970-83. doi:10.1016/j.molcel.2015.07.028. https://pubmed.ncbi.nlm.nih.gov/26344097/