MUL1 is an E3 ligase located in the outer mitochondrial memb...

created [InstanceEdit:9758072] Rothfels, Karen, 2021-11-09
dbId 9758073
displayName MUL1 is an E3 ligase located in the outer mitochondrial memb...
modified [InstanceEdit:9766698] Rothfels, Karen, 2022-02-23
schemaClass Summation
text 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).
Protein levels of UBXN7, in turn, govern the stability and and activity of various cullin E3 ligase complexes, including the VHL:CUL2 ligase complex and the KEAP1:CUL3 ligase complex. Ubiquitination by these CRL cullin ligase complexes promote the degradation of transcription factors such as HIF1alpha and NFE2L2, which play roles in the response to hypoxia and oxidative stress (Iwai et al. 1999, Kamura et al. 2000, Ohh et al. 2000, Groulx and Lee 2002, Maynard et al. 2003; Tao et al, 2017; Itoh et al. 1999, Cullinan et al. 2004, Kobayashi et al. 2004, Zhang et al. 2004, Furukawa & Xiong 2005). High levels of UBXN7 lead to HIF1alpha accumulation, whereas low levels of UBXN7 correlate with an increase in NFE2L2 protein.
By regulating UBXN7 levels in response to reactive oxygen species and hypoxic stress, MUL1 affects the protein levels of HIF1alpha and NFE2L2 and ultimately their targets and may contribute to a switch between glycolysis and oxidative phosphorylation. The role of MUL1 in regulating these factors through UBXN7 protein levels may contribute to the Warburg effect, common in many cancers, where cells switch to glycolysis even in the presence of adequate oxygen. Consistent with this, downregulation of UBXN7 is associated with increased oxidative phosphorylation while high levels of UBXN7 promote glycolysis (Cilenti et al, 2020; Di Gregorio et al, 2021).
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