Reactome | MUL1 ubiquitinates UBXN7

MUL1 ubiquitinates UBXN7

Stable Identifier

R-HSA-9755304

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial outer membrane, cytosol

ReviewStatus

5/5

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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).

Literature References

PubMed ID	Title	Journal	Year
12538644	Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex Lee, EH, Chung, J, Maynard, MA, Qi, H, Ohh, M, Conaway, JW, Kondo, Y, Hara, S, Conaway, RC	J Biol Chem	2003
10878807	Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein Pavletich, N, Kim, TY, Park, CW, Ivan, M, Kaelin, WG, Ohh, M, Huang, LE, Hoffman, MA, Chau, V	Nat Cell Biol	2000
32005965	Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1α) and metabolic reprogramming by modulating the UBXN7 cofactor protein Di Gregorio, J, Zervos, AS, Liao, R, Andl, T, Ambivero, CT, Cilenti, L	Sci Rep	2020
15601839	BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase Furukawa, M, Xiong, Y	Mol. Cell. Biol.	2005
15367669	The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase Jin, J, Harper, JW, Gordan, JD, Diehl, JA, Cullinan, SB	Mol. Cell. Biol.	2004
12101228	Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein Lee, S, Groulx, I	Mol Cell Biol	2002
9887101	Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain Ishii, T, Engel, JD, Yamamoto, M, Igarashi, K, Itoh, K, Katoh, Y, Wakabayashi, N	Genes Dev.	1999
15572695	Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex Zhang, DD, Cross, JV, Hannink, M, Templeton, DJ, Lo, SC	Mol. Cell. Biol.	2004
10973499	Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex Kamura, T, Sato, S, Czyzyk-Krzeska, M, Conaway, JW, Iwai, K, Conaway, RC	Proc Natl Acad Sci U S A	2000
10535940	Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex Kamura, T, Yamanaka, K, Minato, N, Conaway, JW, Klausner, RD, Iwai, K, Conaway, RC, Pause, A	Proc Natl Acad Sci U S A	1999
33444648	UBXN7 cofactor of CRL3^KEAP1 and CRL2^VHL ubiquitin ligase complexes mediates reciprocal regulation of NRF2 and HIF-1α proteins Di Gregorio, J, Zervos, AS, Liao, R, Andl, T, Ambivero, CT, Cilenti, L	Biochim Biophys Acta Mol Cell Res	2021
28115426	p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex Rojo de la Vega, M, Chen, H, Zhang, DD, Luo, G, Tao, S, Chapman, E, Wu, T, Tillotson, J, Liu, P	Mol Cell Biol	2017
15282312	Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2 Yamamoto, M, Kang, MI, Kobayashi, A, Igarashi, K, Chiba, T, Okawa, H, Zenke, Y, Ohtsuji, M	Mol. Cell. Biol.	2004