The best characterized CRL2 substrate binding F-box protein is the von Hippel- Lindau (VHL) tumor suppressor, which targets the alpha subunit of hypoxia inducible factor (HIFalpha) for ubiquitination and degradation through VCP/p97 and the 26 S proteasome (Sufan and Ohh, 2006; Heir et al, 2013; reviewed in Cai and Yang, 2016). UBXN7 is an adapter that binds to neddylated CUL2 and interferes with the ability of the CUL2:EloB:EloC:VHL E3 ubiquitin ligase complex to ubiquitinate HIF alpha, in this way causing accumulation of HIF alpha (Bandau et al, 2012; Den Besten et al, 2012).
MUL1 is an E3 ligase located in the outer mitochondrial membrane with its RING domain facing the cytosol. MUL1 ubiquitinates the cullin scaffold/adaptor protein UBXN7 at lysine residues K14 and K412, promoting its 26S proteasome-dependent degradation (Cilenti et al, 2020, DiGregorio et al, 2021). By inactivating UBXN7, MUL1 activity promotes the CUL2:RBX1-mediated degradation of HIF1 alpha (Di Gregorio et al, 2021).