Fig. 7.

Protein degradation modulates the tumor microenvironment. IKK can be stabilized by CYLD to facilitate the phosphorylation of IκB, which can be reversed by KEAP1-mediated ubiquitylation on IKK. β-TrCP induces activation of the NF-κB pathway by ubiquitinating IκB, resulting in nucleus translocation of the NF-κB complex. β-TrCP and KEAP1 facilitate NRF2 degradation, while USP17 can deubiquitinate NRF2. KEAP1 can also be regulated by DUB USP15. Under hypoxic conditions, HIF-1α can translocate into the nucleus and facilitate transcription of hypoxic genes. While under normoxia, HIF-1α can be oxidated and further ubiquitinated by VHL for degradation. USP22, USP29, and USP14 can deubiquitylate HIF-1α