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USP18 deubiquitinates MAP3K7. 21 / 22
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"These observations suggest that USP18 and USP19 deubiquitinate TAK1 in a cell type specific dependent manner."

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"To further investigate whether deubiquitination of TAK1 by USP18 is required for USP18 protease activity, we generated protease inactive USP18 mutants by substituting a serine residue for cysteine within the catalytic domain (C64S), and by further substituting the conserved histidine residue with alanine at position 318 (C64S H318A)."

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"USP18 deubiquitinates TAK1 in a protease dependent manner in HEK293 cells."

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"Interestingly, in transfection experiments, Usp18 bound to and deubiquitinated Tak1, thereby reducing its kinase activity and the associated downstream signaling."

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"In contrast, they suggest that USP18 inhibits ubiquitination of the TAK1 and TAB1 complex in a protease dependent manner XREF_BIBR, XREF_BIBR."

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"Moreover, USP18 also binds to and deubiquitinates TAK1, thereby promoting hepatic inflammatory responses (90–92)."

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"Furthermore, USP18 was described to negatively regulate TLR-mediated NF-κB signalling: Yang et al. [60] suggested that USP18 inhibits ubiquitination of the TAK/TAB complex and the IKKα/β-NEMO (IκB kinase/NF-κB essential modulator) complex in a protease-dependent or independent manner, respectively."

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"USP4 and USP18 bind with TAK1 and de-ubiquitinate TAK1 to inhibit its activation [10, 12]."

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"USP18 can improve insulin sensitivity by deubiquitinating TAK1 and inhibiting TAK1 phosphorylation to downregulate NF-κB signaling pathway and upregulate fat mass and obesity-related protein (FTO) (153, 154)."

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"USP18 can inhibit the ubiquitination of the TAK1 and TAB complex, thereby inhibiting IL-2 production and promoting IL-17 production and synthesis."

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"Further studies found that USP18, but not its protease inactive form, USP18-C64S, abolished the K63-linked polyubiquitination of TAK1, suggesting that USP18 deubiquitinates TAK1 in a protease-dependent mechanism [38]."

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"USP18 binds to and inhibits ubiquitination of the TAK1 and TAB complex, thereby restricting IL-2 production and promoting IL-17 production."

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"USP18 de-ubiquitinates TAK1, thereby blocking phosphorylation of RCAN1, an inhibitor of calcineurin."

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"Collectively, our findings revealed that USP18 inhibits TAK1 and NEMO ubiquitination through different mechanisms."

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"To further examine whether USP18 deubiquitinates the TAK1 and TAB1 complex, we purified Flag tagged USP18 from 293T cells transiently transfected with Flag-USP18 plasmid by immunoprecipitation with anti-Flag agarose and elution with Flag peptide."

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"Collectively, these data suggest that USP18 targets the TAB1 and TAK1 complex and inhibits TAK1 polyubiquitination modification and kinase activity, thereby restricting TCR mediated NF-kappaB and NFAT activation and subsequent expression of IL-2."

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"USP18 directly cleaves the K63 linked polyubiquitin chains, but not K48 linked polyubiquitin chains from TAK1 in a protease dependent manner since the USP18 catalytically inactive mutant can not deubiquitinate TAK1."

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"Using similar mechanisms of action, deubiquitination of TAK1 by the deubiquitinase USP18 inhibits TCR (Figure 2)."
| PMC

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"We have identified that USP18 promotes deubiquitination of TAK1-TABs complex and inhibits induction of IL-2 after TCR stimulation [105] ."

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"Mechanistically, USP18 interacts with the TAK1-TAB1 complex and deubiquitinates TAK1, thereby restricting TCR-mediated NF-κB and NFAT activation, and subsequent expression of IL-2."

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"Previous studies showed that USP18 potently abolishes the polyubiquitination of TAK1 and TAB1 complex XREF_BIBR."