Table 1.

Host DUBs targeting key molecules in innate immunity

Host targets	DUBs involved	Linkage type	Signaling function	Refs.
Signaling inhibition
MyD88	OTUD4	K63	Inhibiting TLR/NF‐κB signaling	[ 100 ]
TRIF	USP19	K27	Inhibiting TLR3/4‐mediated signaling	[ 98 ]
TRAF6	A20	K63	Terminating TLR‐induced activity	[ 91 ]
	USP4	K63	Preventing NF‐κB and AP1 activation, inhibiting TLR/IL‐1R signaling	[ 102 ]
	USP 10	K63	Interacting with TANK and MCPIP1, terminating NF‐κB activation in response to TLR	[ 104 ]
	MYSM1	K63	Terminating TLR‐mediated antiviral responses	[ 101 ]
	OTUD1	K48	Inhibiting IFN production	[ 175 ]
	OTUB1/2	K63	Inhibiting antiviral responses	[ 172 ]
TRAF3	MYSM1	K63	Terminating TLR‐mediated antiviral responses	[ 101 ]
	UCHL1	K63	Inhibiting IFN production	[ 103 ]
	OTUD1	K48	Inhibiting IFN production	[ 175 ]
	OTUB1/2	K63	Inhibiting antiviral responses	[ 172 ]
RIP1 (also known as RIPK1)	A20	K63	Inhibiting NF‐κB signaling	[ 92 ]
	CYLD	K63	Inhibiting NF‐κB signaling	[ 95 ]
	A20	K48	Inducing A20 degradation with E3 ligase activity, inhibiting NF‐κB signaling	[ 92 ]
NEMO	A20	N/A	Binding to ubiquitinated NEMO, blocking IKK phosphorylation, inhibiting NF‐κB activation	[ 93 ]
	CYLD	M1	Inhibiting NF‐κB signaling	[ 97 ]
	USP10	M1	Interacting with NEMO via MCPIP1, inhibiting the genotoxic NF‐κB signaling	[ 40 ]
TAK1	USP18	K63	Inhibiting TLR/NF‐κB signaling	[ 116 ]
RIG‐I	USP5	K48	Interacting with STUB1, mediating RIG‐I degradation, enhancing VSV replication	[ 174 ]
	CYLD	K63	Inhibiting IFN production	[ 162 ]
	USP3	K63	Inhibiting antiviral responses upon viral infection	[ 164 ]
	USP21	K63	Inhibiting antiviral responses	[ 165 ]
	USP14	K63	Inhibiting antiviral responses	[ 167 ]
	USP27X	K63	Inhibiting antiviral responses	[ 168 ]
	USP15	K63	Inhibiting antiviral responses	[ 169 ]
MAVS	YOD1	K63	Inhibiting IRF3 and p65 activation, IFN‐β production, inhibiting antiviral responses	[ 170 ]
	OTUD1	K48	Inhibiting IFN production	[ 175 ]
	OTUD3	K63	Inhibiting antiviral responses	[ 171 ]
STING	USP49	K63	Inhibiting antiviral responses after HSV‐1 infection	[ 217 ]
	USP21	K63	Inhibiting type I interferon production induced by DNA virus	[ 219 ]
	USP13	K27/33	Impairing the recruitment of TBK1 to STING, inhibiting antiviral responses	[ 218 ]
	USP21	K27	Inhibiting type I interferon production induced by DNA virus	[ 219 ]
	USP22	K27	Interacting with USP13	[ 174 ]
TBK1	A20	K63	Inhibiting antiviral responses with TAX1BP1	[ 232 ]
	USP2b	K63	inhibiting TBK1 kinase activity, terminating TBK1 activation, inhibiting IFN‐β signaling	[ 233 ]
	USP7	K48	Interacting with and stabilizing TRIM27, inhibiting antiviral type I IFN signaling	[ 235 ]
	USP38	K33	Interacting with TBK1 via NLRP4, allowing DTX4‐ and TRIP‐ mediated K48‐linked polyubiquitination, promoting TBK1 degradation, inhibiting IFN‐I signaling	[ 236 ]
IRF3	OTUD1	K63	Inhibiting IRF3 nuclear translocation and its transcriptional activity	[ 244 ]
		K6	Disassociation of IRF3 from the promoter region of target genes, inhibiting type I IFN induction	[ 245 ]
Signaling activation
TRAF3	USP25	K48	Preventing TRAF3 degradation following virus infection, facilitating antiviral responses	[ 117 , 180 ]
	OTUD7B	K48	Inhibiting TRAF3 proteolysis, preventing aberrant non‐canonical NF‐κB activation	[ 118 ]
RIG‐I	USP15	K63	Removing K48‐linked polyubiquitin chains on TRIM25, promoting IFN‐I expression	[ 181 ]
	USP4	K48	Stabilizing RIG‐I, prolonging IFN induction	[ 177 ]
	USP17	K48	Stabilizing RIG‐I, facilitating antiviral responses	[ 176 ]
MAVS	OTUD4	K48	Inhibiting MAVS degradation, triggering antiviral signaling	[ 178 ]
TRAF6	USP4	K48	Inhibiting TRAF6 degradation, inhibiting EV71 replication	[ 179 ]
	USP25	K48	Facilitating antiviral responses	[ 180 ]
cGAS	USP14	K48	Recruited by TRIM14, stabilizing cGAS, facilitating antiviral signaling	[ 207 ]
	USP27x	K48	Stabilizing cGAS, regulating DNA‐mediated signaling	[ 208 ]
	USP29	K48	Stabilizing cGAS, facilitating antiviral responses	[ 209 ]
STING	USP20 (USP18)	K48	Stabilizing STING, promoting antiviral responses after HSV‐1 infection, recruited by USP18 to increase efficiency	[ 212 ]
	CYLD	K48	Stabilizing STING, facilitating antiviral responses	[ 213 ]
	USP44	K48	Stabilizing STING, facilitating antiviral responses upon DNA virus infection	[ 214 ]
TBK1	USP1	K48	Preventing TBK1 degradation, enhancing TLR3/4‐ and RIG‐I‐induced IRF3 activation and IFN‐β secretion	[ 237 ]
p65	USP7	K48	Stabilizing p65, increasing 65 transcription	[ 223 ]
IRF3	USP22	K48	Stabilizing KPNA2, promoting IRF3 nuclear translocation, promoting antiviral responses	[ 246 ]