Table 1 The underlying mechanisms and effects of USP12-substrates interactions
Substrate | Mechanism | Impact | References |
|---|---|---|---|
PHLPP1 | USP12 deubiquitunates and stabilizes PHLPP1, which is an negative regulator of PI3K-Akt pathway, and this effect depends on the interaction between PHLPP1 and the specific domain of WDR48 that between its phosphatase domain and PDZ domain | Induce tumor cell apoptosis and inbibit proliferation | [63] |
PHLPPL/PHLPP | USP12 deubiquitinates and stabilizes PHLPPL/PHLPP, which can decrease pAkt level through dephosphorylating it at S213/S791 site to suppress PI3K/Akt signaling, and then increase AR stability to promote prostate cancer | Deplete Usp12 resulted in the sensitisation of PC cells to Akt inhibition irrespectively of AR status | [107] |
PPM1B | USP12 stabilizes PPM1B via deubiquitinaion, which is considered as an inhibitor of NF-κB pathway by inactivating IKKβ, thus inhibiting NF-κB pathway to negatively regulate cell chemokine expression | Represses NF-κB signaling activity to regulate the production of chemokine like CXCL8, CXCL1 or CCL2 | [66] |
MDK | USP12 mediates MDK deubiquitination by cleaving K48-linked polyubiquitin chains, and then MDK can promote VEGF expression via Akt-mTOR pathway to promote breast cancer angiogenesis and tumorigenesis | Stabilize MDK to activate the Akt-mTOR pathway to promote BC angiogenesis and metastasis | [73] |
BMI-1/c-Myc/cyclin-D2 | USP12 upregulates the transcription of BMI-1, c-Myc and cyclin D2 to promote cell cycle progression, and L153S and R237C mutations significantly increased the USP12 deubiquitinating enzyme activity | Regulate HeLa cell cycle progression positively. Depletion of USP12 impaired cell growth by inhibiting cell cycle progression without causing apoptosis in HeLa cells | [50] |
AR | USP12 stabilizes AR and increases the transcript levels of AR and AR-regulated genes PSA and TMPRSS2 through deubiquitinaion | Promote the proliferation and cell cycle progression of PC, and inhibit PC cells apoptosis | [42] |
Bax | USP12 regulates the K63-linked polyubiquitin chain of Bax through deubiquitinating enzyme activity, and the Bax K189R mutant form has higher ubiquitination level and shorter half-life | Stabilize Bax to promote apoptosis | [69] |
HMGB1 | USP12 deubiquitinates and stabilizes HMGB1, thus inducing autophagy in multiple myeloma | Promote growth and survival of MM cells, and enhance bortezomib resistance in MM | [67] |
mHTT | Usp12 suppress mHTT neuronal toxicity withnot requiring its deubiquitinating activity, suggesting that the functional specificity of Usp12 in suppressing mHTT toxicity is conferred by sequences that reside outside the conserved catalytic domains | Protect neurons through rescuing mHTT-mediated neurodegeneration | [70] |
MMP14 | Circ-ADRM1 recruits USP12 to impede the ubiquitination of MMP14 protein, thereby enhancing the stability of MMP14 protein | Promotes LUAD cell proliferation, invasion and migration through upregulating MMP14 | [74] |
IκBα | USP12 promotes NF-κB signalling in macrophages through the dephosphorylation of IκBα, which is a inhibitor of NFκB nuclear translocation | Promote LPS induced macrophage responses through the inhibition of IκBα | [49] |
LAT/Trat1 | Usp12 stabilizes LAT and Trat through deubiquitylating and preventing their lysosomal degradation | Maintain the proximal TCR complex for the duration of signaling | [45] |
NLRP3 | UAF1-USP12 complexes interact with p65 and inhibit its ubiquitination and degradation, thus promoting NF-κB activation, resulting in the enhancements of NLRP3 | Facilitate NLRP3 inflammasome activation via targeting NLRP3 and p65 | [99] |
STAT1 | USP12 translocates from the cytoplasm to the nucleus and then blocks CBP-induced acetylation of phosphorylated STAT1 (p-STAT1) | Maintain nuclear p-STAT1 levels and IFN antiviral efficacy | [102] |