Fem1b, or Fem1 homolog B, is a substrate recognition subunit for ubiquitin ligase complexes in the CULLIN 2-based E3 family. It plays a crucial role in the ubiquitin-proteasome system, determining the specificity of protein degradation. FEM1B is involved in pathways such as the reductive stress response, where it helps cells maintain redox homeostasis by regulating mitochondrial activity [2,3]. It also has implications in biological processes related to angiogenesis and oxidative stress modulation [1].

In relation to disease, a recurrent de novo missense variant in FEM1B (p.(Arg126Gln)) was found to cause a severe syndromic neurodevelopmental disorder. Overexpression of this variant during mouse brain development led to delayed neuronal migration, and patient cells showed signs of oxidative stress and induction of type I interferon signaling [4]. In cancer, miR-29a-3p was shown to downregulate FEM1B expression, conferring oxaliplatin resistance in colorectal cancer cells. FEM1B targets Gli1 for degradation, and reduced FEM1B levels led to increased Gli1 levels contributing to drug tolerance [5].

In conclusion, Fem1b is essential in regulating protein degradation through the ubiquitin-proteasome system, with a key role in the reductive stress response and redox homeostasis. Studies using genetic models, such as in the context of the human missense variant in mouse brain development, have revealed its importance in neurodevelopmental disorders. In cancer, its role in drug resistance mechanisms provides insights into potential therapeutic targets.

References:

1. Zhang, Wenqian, Zha, Kangkang, Xiong, Yuan, Mi, Bobin, Liu, Guohui. 2023. Glucose-responsive, antioxidative HA-PBA-FA/EN106 hydrogel enhanced diabetic wound healing through modulation of FEM1b-FNIP1 axis and promoting angiogenesis. In Bioactive materials, 30, 29-45. doi:10.1016/j.bioactmat.2023.07.006. https://pubmed.ncbi.nlm.nih.gov/37521275/

2. Manford, Andrew G, Mena, Elijah L, Shih, Karen Y, Kuriyan, John, Rape, Michael. 2021. Structural basis and regulation of the reductive stress response. In Cell, 184, 5375-5390.e16. doi:10.1016/j.cell.2021.09.002. https://pubmed.ncbi.nlm.nih.gov/34562363/

3. Manford, Andrew G, Rodríguez-Pérez, Fernando, Shih, Karen Y, Nomura, Daniel K, Rape, Michael. 2020. A Cellular Mechanism to Detect and Alleviate Reductive Stress. In Cell, 183, 46-61.e21. doi:10.1016/j.cell.2020.08.034. https://pubmed.ncbi.nlm.nih.gov/32941802/

4. Lecoquierre, François, Punt, A Mattijs, Ebstein, Frédéric, Elgersma, Ype, Vitobello, Antonio. 2024. A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder. In Genetics in medicine : official journal of the American College of Medical Genetics, 26, 101119. doi:10.1016/j.gim.2024.101119. https://pubmed.ncbi.nlm.nih.gov/38465576/

5. Su, Yi-Chen, Metzen, Landon Tyler, Vélez, Leandro Martín, Huang, Chih-Yang, Kaiser, Peter. 2023. Induction of resistance to oxaliplatin in cancer by a microRNA/Fem1B/Gli1 pathway. In American journal of cancer research, 13, 6011-6025. doi:. https://pubmed.ncbi.nlm.nih.gov/38187042/