TABLE 3.

Examples of viral regulators of STAT3^a

Virus	Effect on STAT3	Reference(s)
EBV	EBV proteins LMP1, LMP2A, and EBNA2 upregulate STAT3 signaling to promote cell growth/transformation and viral gene expression/latency and inhibit autophagy. STAT3 binds and activates transcription from promoters of LMP1 and EBNA1 in the viral genome.	37–41, 73, 74, 236–239
HBV	HBV X protein promotes STAT3 activation through interaction with JAK1, deregulation of cellular miRNA expression, and induction of reactive oxygen species. HBV infection activates STAT3 through IL-6-dependent pathways. STAT3 activation impacts viral gene expression/replication, cell survival/proliferation, and apoptosis. STAT3 binds and activates transcription from enhancer 1 in the viral genome.	47–53
HPV	HPV E6 upregulates IL-6/STAT3 signaling to promote viral gene expression and tumorigenesis. STAT3 binds the upstream regulatory region in the viral genome.	240–243
Varicella-zoster virus	Varicella-zoster virus upregulates miR-21 to enhance STAT3 signaling, promoting cell survival and virus replication.	192, 244
Rift Valley fever virus	Rift Valley fever virus NSs induces STAT3 activation to promote cell survival and inhibit virus-induced cell death.	245
PEDV	PEDV upregulates EGFR/STAT3 signaling to inhibit type I IFN signaling and promote viral replication.	55
KSHV	KSHV upregulates STAT3 signaling, including through binding of KSHV LANA and RTA to STAT3 and through JAK-dependent pathways. KSHV kaposin B induces monophosphorylation of STAT3 at S727. STAT3 signaling promotes cell transformation, latency, and inflammatory responses and inhibits autophagy.	43, 75, 141–146, 181
	KSHV cyclin K binds STAT3 and inhibits growth-suppressive effects of OSM. KSHV encodes miRNAs that inhibit IL-6/IFN-α-induced STAT3 activation/target gene expression. STAT3 inhibition may induce lytic reactivation.	106, 246, 247
HCV	HCV upregulates STAT3 signaling, including through binding of HCV core to STAT3, upregulation of IL-6, and induction of reactive oxygen species. STAT3 activation deregulates inflammatory responses and promotes cell proliferation/transformation and viral replication.	63–68
	HCV blocks STAT3-DNA binding and induces proteasomal degradation of STAT3, inhibiting IFN-α/LIF signaling.	69, 70
HCMV	HCMV US28 upregulates IL-6/STAT3 signaling to promote cell proliferation/transformation. STAT3 activity is required for efficient viral gene expression/replication.	71, 193, 248
	HCMV IE1 binds and sequesters unphosphorylated STAT3 in the nucleus, inhibiting IL-6/STAT3-dependent gene expression and rewiring IL-6 signaling into an IFN-γ-like response. HCMV inhibits STAT3 activation in response to IFN-α/γ.	71, 72, 249
HIV-1	HIV-1 Nef and gp120 upregulate soluble factors that activate STAT3, potentially promoting cell survival and deregulating inflammatory responses. HIV-1 induces monophosphorylation of STAT3 at S727. HIV-1 upregulates IL-10/STAT3 signaling in bystander cells to inhibit autophagy.	76, 156, 180, 250
	HIV-1 Vif induces proteasomal degradation of STAT3, inhibiting IFN-α signaling.	251
EV71	EV71 induces STAT3 activation to inhibit type I IFN signaling and promote viral replication.	54
	EV71 induces miRNA-124, which suppresses IL-6/STAT3 signaling to inhibit anti-EV71 activity. EV71 induces proteasomal degradation of STAT3.	54, 252
RABV	RABV induces miRNA-455, which suppresses SOCS3 and enhances STAT3 activation to promote viral replication.	253
	RABV P protein selectively binds IFN-α/OSM-activated STAT3-STAT1 heterodimers to inhibit nuclear accumulation and target gene expression.	155, 189
IAV	IAV induces STAT3 activation to delay apoptosis.	254
	IAV inhibits STAT3 activation in response to IFN-β/IL-6 by upregulating SOCS3 and downregulating IFN receptor. Inhibition of IL-6/STAT3 signaling is associated with disease severity in vivo.	154, 255
Severe acute respiratory syndrome coronavirus 1	Severe acute respiratory syndrome coronavirus 1 PLpro promotes STAT3 signaling to upregulate the Egr-1/TGF-β1b fibrotic pathway.	256
	Severe acute respiratory syndrome coronavirus 1 reduces STAT3 phosphorylation, potentially promoting apoptosis.	257
MUV	MUV V protein induces proteasomal degradation of STAT3, inhibiting IL-6/v-Src/STAT3-dependent gene expression. STAT3 antagonism is associated with disease severity in vivo.	57, 59
MEV	MEV V protein binds STAT3, inhibiting IL-6/v-Src/STAT3-dependent gene expression.	58
Tioman virus	Tioman virus V protein binds STAT3, inhibiting IL-6/STAT3-dependent gene expression.	62
PRRSV	PRRSV NSP5 induces proteasomal degradation of STAT3, inhibiting OSM/STAT3-dependent gene expression.	258
Hepatitis E virus	Hepatitis E virus ORF3 disrupts EGF receptor trafficking, inhibiting EGF/STAT3-dependent gene expression.	259
Marburg virus	Marburg virus VP40 inhibits JAK1 phosphorylation, suppressing IL-6-induced STAT3 activation.	231
Human metapneumovirus	Human metapneumovirus inhibits JAK2 phosphorylation, suppressing IL-6/STAT3-dependent gene expression.	260
Adenovirus	Adenovirus inhibits JAK1 phosphorylation, suppressing IL-6/OSM-induced STAT3 activation.	233

^aLightface and boldface indicate stimulatory and inhibitory effects, respectively, on STAT3.

^bTGF-β1, transforming growth factor β1.