WDSUB1, an E3 ligase, is involved in multiple biological processes. It contains a U box domain, and is thought to have emerged in placozoans, cnidarians, and bilaterians during evolution [3]. In the context of the ankle-link complex (ALC), WDSUB1 binds to WHRN and regulates the ubiquitination of USH2A in a WHRN phosphorylation-dependent manner. ADGRV1 can inhibit WHRN phosphorylation, which in turn regulates USH2A ubiquitination and stability via local signaling compartmentalization. However, a deafness-associated ADGRV1 mutation disrupts this process through improper WHRN phosphorylation and WDSUB1 recruitment, leading to stereocilia disorganization and mechanoelectrical transduction deficits [1].

In mouse models, knockdown of WDSUB1 alleviates dextran sulfate sodium-induced colitis. Mice with WDSUB1 knockdown showed milder weight loss, diarrhea, and hematochezia, along with lower expressions of inflammatory factors such as COX2, IL-6, and TNFα. This effect may be achieved by inhibiting the NF-κB signaling pathway [2].

In summary, WDSUB1 plays crucial roles in processes related to hair cell development in the inner ear, potentially linked to deafness, and in colonic inflammation. Studies using mouse models, like knockdown in the context of colitis, have provided insights into its functions in disease-relevant biological processes, highlighting its importance in understanding the mechanisms of these diseases.

References:

1. Guan, Ying, Du, Hai-Bo, Yang, Zhao, Sun, Jin-Peng, Xu, Zhi-Gang. 2023. Deafness-Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2205993. doi:10.1002/advs.202205993. https://pubmed.ncbi.nlm.nih.gov/37066759/

2. Wang, S, Cui, L, Liu, X, Li, H, Pu, J. . [WDSUB1 knockdown alleviates dextran sulfate sodium-induced colitis in mice by inhibiting nuclear factor-κB signaling pathway]. In Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 42, 1119-1125. doi:10.12122/j.issn.1673-4254.2022.08.02. https://pubmed.ncbi.nlm.nih.gov/36073209/

3. Marín, Ignacio. 2010. Ancient origin of animal U-box ubiquitin ligases. In BMC evolutionary biology, 10, 331. doi:10.1186/1471-2148-10-331. https://pubmed.ncbi.nlm.nih.gov/20979629/