Fbxo6, also known as FBG2, is a component of the ubiquitin E3 ligases. It binds high mannose N-linked glycoproteins and acts as a substrate recognition subunit of the SCF (Skp1-Cul1-F-box protein) complex, playing a role in ubiquitination and degradation of target proteins, which is involved in multiple biological processes and disease-related pathways [1].

In osteoarthritis (OA), global or conditional knockout of Fbxo6 in cartilage promoted the experimental OA process. Fbxo6 deficiency led to increased MMP14 levels due to reduced ubiquitination and degradation, activating MMP13 and enhancing cartilage extracellular matrix degradation. TGFβ-SMAD2/3 signaling upregulates Fbxo6 transcription to suppress MMP13 activation [1].

In influenza A virus (IAV) infection, Fbxo6-deficient mice showed decreased pulmonary viral replication, alleviated pulmonary dysfunction, and less mortality. Fbxo6 promotes proteasomal degradation of NLRX1, facilitating IAV-induced alveolar macrophages apoptosis and modulating macrophage survival and type I interferon signaling [2].

In ovarian cancer, FBXO6 promotes K48-dependent ubiquitination and degradation of RNASET2, a tumor suppressor. High FBXO6 expression in ovarian cancer tissues is related to poor overall survival, and FBXO6 depletion promotes cancer cell proliferation, migration, and invasion [3].

In summary, Fbxo6 is crucial in regulating multiple biological functions. Gene knockout (KO) and conditional knockout (CKO) mouse models have revealed its significant roles in diseases like OA, IAV-related immune response, and ovarian cancer. These findings contribute to understanding the disease mechanisms and may provide potential therapeutic strategies for these diseases.

References:

1. Wang, Gangliang, Chen, Shuai, Xie, Ziang, Qin, An, Fan, Shunwu. 2020. TGFβ attenuates cartilage extracellular matrix degradation via enhancing FBXO6-mediated MMP14 ubiquitination. In Annals of the rheumatic diseases, 79, 1111-1120. doi:10.1136/annrheumdis-2019-216911. https://pubmed.ncbi.nlm.nih.gov/32409323/

2. Cen, Mengyuan, Ouyang, Wei, Lin, Xiuhui, Qin, Xiaofeng, Xu, Feng. 2022. FBXO6 regulates the antiviral immune responses via mediating alveolar macrophages survival. In Journal of medical virology, 95, e28203. doi:10.1002/jmv.28203. https://pubmed.ncbi.nlm.nih.gov/36217277/

3. Ji, Mei, Zhao, Zhao, Li, Yue, Huang, Xiaotian, Liu, Bin. 2021. FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer. In Cell death & disease, 12, 317. doi:10.1038/s41419-021-03580-4. https://pubmed.ncbi.nlm.nih.gov/33767133/

4. Chen, Xi, Duan, Lang-Huan, Luo, Peng-Cheng, Lu, Han, Liu, Bin. 2016. FBXO6-Mediated Ubiquitination and Degradation of Ero1L Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis. In Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 39, 2501-2508. doi:. https://pubmed.ncbi.nlm.nih.gov/27855403/