Table 3.

The roles of DUBs in immunity.

DUB	Effect	Target	Linkage	Rationale
TLRs signaling
USP4	Inhibition	TRAF6	Lys63	Prevent NF‐κB and AP1 signaling[ 187 ]
USP10	Inhibition	TRAF6	Lys63	Terminate NF‐κB signaling[ 530 ]
	Inhibition	NEMO	Met1	Terminate NF‐κB signaling[ 531 ]
USP18	Inhibition	TAK1, NEMO	Lys63	Inhibit TLR/NF‐κB signaling[ 182 ]
USP19	Inhibition	TRIF	Lys27	Inhibit TLR3/4 signaling[ 532 ]
USP25	Activation	TRAF3/6	Lys48	Stabilize TRAF3, promote Antiviral Res..ponses[ 190 , 191 ]
OTUB1/2	Inhibition	TRAF3/6	Lys63	Inhibit Antiviral Res..ponses[ 533 ]
OTUD1	Inhibition	TRAF3/6	Lys48	Stabilize Smurf1, and promotes the Smurf1‐mediated degradation of MAVS, TRAF3/6[ 534 ]
		RIPK1	Lys63	Inhibit RIPK1‐mediated NF‐κB signaling to suppress colonic inflammation[ 185 ]
OTUD4	Inhibition	MyD88	Lys63	Inhibit TLR‐mediated NF‐κB signaling[ 186 ]
OTUD7B	Inhibition	TRAF3	Lys48	Prevent aberrant non‐canonical NF‐κB activation[ 189 ]
MYSM1	Inhibition	TRAF3/6	Lys63	Terminate TLR‐induced Antiviral Res..ponses[ 535 ]
A20	Inhibition	TRAF6	Lys63	Terminate TLR/NF‐κB activation[ 180 ]
		NEMO	N/A	Block IKK phosphorylation, or inhibiting NF‐κB activation[ 181 , 536 ]
UCHL1	Inhibition	TRAF3	Lys63	Inhibit p65 phosphorylation and NF‐κB signaling[ 188 ]
CYLD	Inhibition	NEMO	Met1	Inhibit NF‐κB signaling[ 184 ]
RLRs signaling
USP3	Inhibition	RIG‐I	Lys63	Inhibit type I IFN signaling[ 207 ]
USP4	Activation	RIG‐I	Lys48	Stabilize RIG‐I, sustain IFN induction[ 214 ]
	Activation	TRAF6	Lys48	Stabilize TRAF6, inhibit EV71 replication[ 537 ]
USP5	Inhibition	RIG‐I	Lys11/48	Induce RIG‐I degradation[ 233 ]
USP14	Inhibition	RIG‐I	Lys63	Inhibit RIG‐I‐triggered type I IFN signaling[ 208 ]
USP15	Inhibition	RIG‐I	Lys63	Inhibit RIG‐I signaling[ 209 ]
	Activation	TRIM25	Lys48	Stablize TRIM25, then enhance the TRIM25‐ and RIG‐I‐dependent type I IFN production[ 212 ]
USP17	Activation	RIG‐1	Lys48	Stabilize RIG‐I, boost Antiviral Res..ponses[ 213 ]
USP21	Inhibition	RIG‐I	Lys63	Inhibit RIG‐I‐dependent Antiviral Res..ponses[ 210 ]
USP27X	Inhibition	RIG‐I	Lys63	Inhibit RIG‐I‐dependent Antiviral Res..ponses[ 211 ]
CYLD	Inhibition	RIG‐I, TBK1	Lys63	Inhibit RIG‐I‐dependent Antiviral Res..ponses[ 206 ]
OTUD2	Inhibition	MAVS	Lys63	Inhibit IRF3, p65 activation, and IFN‐β production[ 538 ]
OTUD3	Inhibition	MAVS	Lys63	Inhibit Antiviral Res..ponses[ 539 ]
OTUD4	Activation	MAVS	Lys48	Stablize MAVS, induce antiviral signaling[ 215 ]
cGAS signaling
USP1	Activation	TBK1	Lys48	Stablize TBK1, enhance IFN‐β secretion[ 540 ]
USP2	Inhibition	TBK1	Lys63	Inhibit TBK1 activation[ 541 ]
USP7	Inhibition	TBK1	Lys48	Stabilize TRIM27, inhibit type I IFN signaling[ 542 ]
	Activation	p65	Lys48	Stabilize p65[ 543 ]
USP13	Inhibition	STING	Lys27/33	Disrupt the interaction between STING and TBK1, inhibit Antiviral Res..ponses[ 231 ]
USP14	Activation	cGAS	Lys48	Stabilize cGAS, facilitate antiviral signaling[ 222 ]
USP20	Activation	STING	Lys48	Stabilize STING, promote Antiviral Res..ponses[ 225 ]
USP21	Inhibition	STING	Lys27/63	Inhibit type I IFN production[ 232 ]
USP22	Inhibition	STING	Lys27	Cooperate with USP13, inhibit Antiviral Res..ponses[ 233 ]
	Activation	IRF3	Lys48	Stabilize importin KPNA2 to facilitate IRF3 nuclear translocation[ 544 ]
USP27X	Activation	cGAS	Lys48	Stabilize cGAS, govern DNA‐mediated signaling[ 223 ]
USP29	Activation	cGAS	Lys48	Stabilize cGAS, facilitate antiviral signaling[ 545 ]
USP38	Inhibition	TBK1	Lys33	Promote TBK1 degradation through NLRP4 signalosome[ 546 ]
USP44	Activation	STING	Lys48	Stabilize STING, facilitate antiviral signaling[ 227 ]
USP49	Inhibition	STING	Lys63	Inhibit STING aggregation and TBK1 recruitment[ 230 ]
A20	Inhibition	TBK1	Lys63	Cooperate with TAX1BP1 to disrupt TRAF3‐TBK1‐IKKi signaling complex[ 547 ]
OTUD1	Inhibition	IRF3	Lys6/63	Inhibit IRF3 nuclear translocation and DNA binding capacity[ 548 , 549 ]
CYLD	Activation	STING	Lys48	Stabilize STING, facilitate antiviral signaling[ 226 ]
Th1 and Th17 responses
Trabid	Activation	JMJD2D	Lys29	Promote the production of the Th1 and Th17 subsets of inflammatory T cells[ 237 ]
Cezanne	Activation	ZAP70	Lys48	Facilitate ZAP activation and inducing TCR signaling[ 239 ]
USP4	Activation	RORγt	Lys48	Stabilize RORγt, induce rheumatic heart disease[ 236 ]
USP10	Activation	T‐bet	Lys48	Stabilize T‐bet in Th1 cells, induce asthma[ 240 ]
USP17	Activation	RORγt	Lys48	Positive regulator of RORγt in Th17 cells[ 550 , 551 , 552 ]
USP18	Activation	TAK1	Lys63	Induce differentiation of Th17 cells and cytokines secretion[ 238 ]
Treg responses
USP7	Inhibition	FOXP3	Lys48	Stabilize FOXP3 in Treg cells, inhibit TNFα‐stimulated NF‐κB activity[ 256 , 543 , 553 ]
USP21	Activation	GATA3	Lys48	Stabilize GATA3 in Treg cells, limit inflammatory responses[ 543 , 553 ]