Reactome | VHL:EloB,C:NEDD8-CUL2:RBX1 complex binds UBXN7

VHL:EloB,C:NEDD8-CUL2:RBX1 complex binds UBXN7

Stable Identifier

R-HSA-8956099

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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VHL:EloB,C:NEDD8-CUL2:RBX1 complex binds UBXN7

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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).

Literature References

PubMed ID	Title	Journal	Year
23401859	DCNL1 functions as a substrate sensor and activator of cullin 2-RING ligase Heir, P, Sufan, RI, Greer, SN, Poon, BP, Lee, JE, Ohh, M	Mol. Cell. Biol.	2013
17132228	Role of the NEDD8 modification of Cul2 in the sequential activation of ECV complex Sufan, RI, Ohh, M	Neoplasia	2006
22466964	NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway den Besten, W, Verma, R, Kleiger, G, Oania, RS, Deshaies, RJ	Nat. Struct. Mol. Biol.	2012
32005965	Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1α) and metabolic reprogramming by modulating the UBXN7 cofactor protein Cilenti, L, Di Gregorio, J, Ambivero, CT, Andl, T, Liao, R, Zervos, AS	Sci Rep	2020
27222660	The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions Cai, W, Yang, H	Cell Div	2016
33444648	UBXN7 cofactor of CRL3^KEAP1 and CRL2^VHL ubiquitin ligase complexes mediates reciprocal regulation of NRF2 and HIF-1α proteins Di Gregorio, J, Cilenti, L, Ambivero, CT, Andl, T, Liao, R, Zervos, AS	Biochim Biophys Acta Mol Cell Res	2021
22537386	UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation Bandau, S, Knebel, A, Gage, ZO, Wood, NT, Alexandru, G	BMC Biol.	2012