Table 1.

Available two-component system (TCS) sensors. Often, numerous TCSs sense a given input and a given response regulator regulates numerous output promoters. In these cases, one well-characterized TCS or output promoter is listed for simplicity.

Input	Native organism(s)	SHK	RR	Output promoter	Performance notes	Reference
Light
UV-violet light	Synechocystis PCC6803	UirS	UirR	PcsiR1	5-fold activationAlso reported to sense ethylene	[54]
Blue light	B. subtilis, B. japonicum	YF1	FixJ	PfixK2	Chimeric YtvA-FixL SHK. 460-fold activation when coupled to transcriptional inverter (pDushk system)	[80]
Green light	Synechocystis PCC6803	CcaSmini#10	CcaR	PcpcG2-172	600-fold activation	[81]
Red light	Synechocystis PCC6803, E. coli	Cph8*	OmpR	PompF112	80-fold de-activation	[60]
Near infrared light	Rps. palustris, B. japonicum BTAi1	BphP1	PpsR2	PBr_crtE	Signaling based on RR sequestration. 2-fold activation	[62]
Temperature
25°C	B. subtilis	DesK	DesR	Pdes	Fully activated and repressed at 25°C and 37°C, respectively	[82]
pH
Acidic pH (<6.2)	S. oneidensis, B. subtilis	SO_4387	SO_4388REC-PsdRDBD 137	PpsdA110	Used to sense small intestinal inflammation in mice	[52,61]
Acidic pH (extracellular)	H. pylori	ArsS	ArsR	PamiE, PamiF	Activated in the human stomach	[83,84]
Metals
As3+ (extracellular)	A. tumefaciens	AioS	AioR	PaioB	Requires AioX inner membrane accessory protein	[85]
Ca2+ (extracellular)	P. aeruginosa PAO1	CarS	CarR	PcarO	CarS is related to PhoQ but senses the presence not absence of the divalent cation	[86]
Cu+ (extracellular)	E. coli	CusS	CusR	PcusC	Also activated by Ag (I)	[87-89]
Cu2+ (extra- and intracellular)	Synechocystis PCC 6803	CopS	CopR	PcopM	CopS partially localizes to thylakoid membranes	[90]
Cu2+ (extracellular)	M. xanthus	CorS	CorR	PcuoA		[91]
Fe2+, Fe3+ (extracellular)	S. marcescens	RssA	RssB	PpvcA	Activity can be tuned with the natural product 2-isocyano-6,7-dihydroxycoumarin	[92]
K+ (extracellular, intracellular)	E. coli	KdpD	KdpE	PkdpF	Inactivated by K+	[93,94]
Ni2+	Synechocystis PCC6803	NrsS	NrsR	PnrsB	10-fold activation. Also weakly activated by Co2+	[95]
U	E. coli	UzcS	UzcR	PurcA	Sensitivity and specificity improved by coupling to UrpRS via AND gate	[96]
Zn2+	E. coli	ZraS	ZraR	PzraP	PzraP is σ54-dependent	[97]
Nutrient availability
Nitrogen limitation	E. coli	NtrB	NtrC	Pddp	Requires the accessory protein GlnBog1.	[98]
Respiratory electron acceptors
O2	S. meliloti	FixL	FixJ	PnifA	O2 inhibits pathway. O2 binds FixL via covalently attached heme.	[99]
Thiosulfate	S. halifaxensis	ThsS	ThsR	PphsA342	Activated proportional to DSS-induced inflammation in mouse colon	[36]
Tetrathionate	S. baltica	TtrS	TtrR	PttrB185-269	100-fold dynamic range	[36]
Nitrate	E. coli	NarX	NarLREC-YdfIDBD 131	PydfJ115	1300-fold activation in B. subtilis.	[61]
Nitrate OR Nitrite	E. coli	NarQ	NarP	PnrfA	NarQ also responds to nitrate. NarX cross-phosphorylates NarP. NarL binds NarP output promoters.	[100]
Trimethyl amine N-oxide (TMAO)	E. coli	TorS	TorRREC-PsdRDBD 137	PpsdA110	DBD swapping eliminates O2 cross repression at native output promoter. Requires periplasmic TorT accessory protein	[61]
Oxidizing agents
O2, H2O2, NO	S. aureus	AirS	AirR	PcrtO	AirS requires a [2Fe–2S]2+ cluster	[101,102]
Small molecule metabolites
α-ketoglutarate (extracellular)	P. aeruginosa PAO1	MifS	MifR	PPA5530	10-fold activation. Weak response to glutarate	[103]
Butanol	C. acetobutylicum	BtrK	BtrR	PbtrT	Involved in butanol tolerance	[104]
C4-dicarboxylates (extracellular)	E. coli	DcuS	DcuR	PfrdA	22-fold activation	[105]
Citrate	K. pneumoniae	CitA	CitB	PcitC	Requires anaerobic conditions	[106]
Fucose	E. coli	Fushk	FusR	Pz0461	Fucose represses transcriptional output	[107]
Fumarate	E. coli	DcuSZ	OmpR	PompC	Chimeric DcuS-EnvZ SHK. < 5-fold activation	[66]
Glucose-6-phosphate	E. coli	UhpB	UhpA	PuhpT99	Requires UhpC inner-membrane accessory protein	[61,108]
l-Glutamate	P. aeruginosa PAO1	AauS	AauR	PaatJ	Very weakly activated by aspartate, glutamine, and asparagine	[109]
Heme (extracellular)	S. aureus	HssS	HssR	PhrtA	>100-fold activation	[110]
Indole	E. coli	BaeS	BaeR	PacrD	Presence of CpxAR TCS amplified the indole response	[111]
Malate	B. subtilis	YufL	YufM	PmaeN381	100-fold activation	[112]
Methanol	P. denitrificans/E. coli	FlhS-EnvZ	OmpR	PompC	2-fold activation	[65]
Pyruvate (extracellular)	E. coli	BtsS	BtsR	PyjiY	Active in uropathogenic E. coli during urinary-tract infections	[113]
Ribose	E. coli	Trg-EnvZ	OmpR	PompC	Chimeric SHK. 20-fold activation	[71]
d-xylose (extracellular)	C. beijerinckii	LytS	YesN	PxylF	d-xylose recognized by outer membrane transporter-like protein XylFII	[114]
Styrene	Pseudomonas sp.strain Y2	StyS	StyR	PstyA	StyS has non-canonical HK-REC-HK structure	[115]
Inter-bacterial communication signals
AIP-I (autoinducer peptide)	S. aureus	AgrC	AgrA	PagrB	AIP-II inhibits AgrC kinase activity	[116]
CAI-1 ((S)-3-hydroxytridecan-4-one)	V. cholerae	CqsS	LuxO	Ptpqrr4	Requires intermediate phosphotransfer protein LuxU	[117]
CSP (Competence Stimulating Peptide)	S. gordonii	ComD	ComE	PcomC		[118]
ComX (extracellular pheromone)	B. subtilis	ComP	ComA	PsrfA		[119]
Antibiotics
β-lactams	V. cholerae	VxrA	VxrB	PmurJ	Generally activated by cell envelope damage	[120]
Linearmycins (intra-membrane)	B. subtilis	LnrJ	LnrK	PlnrL	Can also detect the antifungal polyene amphotericin B.	[121,122]
Vancomycin (extracellular)	S. coelicolor	VanS	VanR	PvanJ	Phosphorylated VanR additionally activates the VanSR operon	[123]
Antimicrobial peptides
Antimicrobial peptides produced by the oral pathogen S. mutans (extracellular)	Streptococcus sp.A12	PcfK	PcfR	PpcfF	Nearly 100-fold activation	[124]
Bacitracin (extracellular)	B. subtilis	LiaS	LiaR	PliaI(opt)	1000-fold activation. Activation occurs in a 1–2 h pulse. Requires accessory membrane protein LiaF.	[125]
Nisin (extracellular)	L. lactis	Nishk	NisR	PnisA	1000-fold activation.	[126]
Subtilin (extracellular)	B. subtilis	SpaK	SpaR	PspaS	110-fold induction	[126,127]
Oligosaccharides
Arabinogalactan	B. thetaiotaomicron	BT0267	BT0267	PBT0268	BT0267 is a hybrid TCS wherein the SHK and RR are fused	[128]
Chondroitin sulfate	B. thetaiotaomicron	BT3334	BT3334	PBT3324	BT3334 is a hybrid TCS	[128]
Mucin glycans	P. aeruginosa	GacS	GacA	PrsmY	Mucin glycans are sensed via the accessory histidine kinase RetS	[129]
Oligo-Arabinose	B. thetaiotaomicron	BT0366	BT0366	PBT0365	BT0366 is a hybrid TCS	[130]
Proteins
PilA	P. aeruginosa	PilS	PilR	PpilA	PilA is the major Type IV pilin protein	[131]
Host signals
Antimicrobial peptides, divalent cation limitation, and acidic pH produced by mammalian hosts during infection	S. Typhimurium	PhoQ	PhoP	PvirK	70-fold activation in E. coli	[132]
Epinephrine, norepinephrine	E. coli O157:H7	QseC	QseB	PflhD	2-fold activation by epinephrine. 1.5-fold repression by norepinephrine. Also activated by bacterial autoinducer 3.	[133]
Indole-3-acetic acid (auxin)	P. phytofirmans PsJN	IacS	IacR1	PiacA	Dioxindole-3-acetic acid amplifies the signal	[134]
2-isopentenyladenine (cytokinin)	X. campestris	PcrK	PcrR	PctrA	3-fold induction	[135]
Phenolics, monosaccharides, and acidic pH present at plant wounds	A. tumefaciens	VirA	VirG	Pvir	Monosaccharide sensing requires the periplasmic accessory protein ChvE.	[136]
Trans-zeatin (cytokinin)	A. thaliana, E. coli	AQ4*	PhoP4*	PmgrB	AQ4* is a fusion of the sensing domain of A. thaliana AHK4 and E. coli PhoQ. This TCS is insulated against phosphorylation cross-talk with all E. coli TCSs	[70]