Table 1.

Moonlighting proteins reported in Rickettsiales.

Organism	Protein	Activity	References
Anaplasma phagocytophilum	Enolase	Converts 2-phosphoglycerate to phosphoenolpyruvate in glycolysis Binds and activates plasminogen	[78,79]
	UMPK	Catalyzes the conversion of uridine monophosphate to uridine diphosphate in the cytoplasm Binds Rab10	[80]
	AnkA	Interacts with CYBB promoter and downregulates expression of CYBB and other host defense genes Binds high-content AT DNA regions and recruits HDAC1 to repress gene expression Undergoes tyrosine phosphorylation by Src kinase and interacts with neutrophil SHP-1, interfering with host cell signaling Binds adaptor protein Abi-1 and is phosphorylated by Abl-1 Interacts with actin and actin-regulating proteins α-actinin 4 and gelsolin	[83,84,85,86,87]
	Ats-1	Inhibits apoptosis in mammalian cells by inhibiting cytochrome c release and PARP cleavage Inhibits Bax-induced apoptosis in yeast cells Binds Beclin 1 and Atg14L, inducing autophagosome formation	[88,91]
	GroEL	Assists protein folding and response to stress Binds to I. scapularis tick cells, presenting a role in A. phagocytophilum-vector interaction. Interacts with HSP70 and MSP4	[92]
	HSP70	Assists protein folding and response to stress Binds to I. scapularis tick cells, presenting a role in A. phagocytophilum-vector interaction. Interacts with GroEL and MSP4	[92]
Ehrlichia chaffeensis	TRP120	Interacts with Wnt and Notch receptors to activate both pathways, regulating apoptosis and autophagy Modulates the expression of several genes Interacts with GC-rich regions of DNA Targets host proteins to degradation, regulating signaling pathways	[93,95,96,97]
	Ank200	Targets transcriptional factors, genes of the epigenetic machinery and components of signaling pathways Interacts with genes related to vesicular trafficking and cytoskeleton proteins Potentially contributes to the delivery of nutrients to ehrlichial inclusions	[94]
	Etf-1	Inhibits apoptosis in mammalian cells and yeast Increases mitochondrial MnSod Decreases ROS, preventing cellular damage and apoptosis Modulates autophagy by recruiting GTP-bound RAB5 and binding VPS34 and Beclin1	[98,100]
Orientia tsutsugamushi	ScaC	Mediates transport to the cell surface Mediates adhesion in non-phagocytic mammalian cells Binds fibronectin	[101]
	ScaB	Mediates transport to the cell surface Mediates adhesion and invasion into epithelial and non-epithelial cells	[102]
	ScaA	Mediates transport to the cell surface Mediates adhesion in non-phagocytic mammalian cells	[103]
	Ank1A	Interacts with SKP1 Interacts with EF-1α	[104]
	Ank1B	Interacts with Cullin1 and SKP1 Interacts with EF-1α	[104]
	Ank1E	Interacts with Cullin1 and SKP1 Interacts with EF-1α	[104]
	Ank1U4	Interacts with Cullin1 and SKP1 Interacts with EF-1α	[104]
	Ank1U5	Interacts with Cullin1 and SKP1 Decreases EF-1α protein level	[104]
	Ank1U9	Interacts with Cullin1 and SKP1 Interacts with EF-1α	[104]
	Ank4	Interacts with SKP1 Nucleates SCF1 ubiquitin ligase complex Induces UPR and inhibits ERAD, contributing bacterial obtaining of ERAD-derived amino acids Binds Bat3	[105]
	Ank1	Decreases NF-κB dependent gene expression by interacting with importin β1, p65 and exportin Interacts with SCF1 complex assembly	[106]
	Ank6	Decreases NF-κB dependent gene expression by interacting with importin β1, p65 and exportin Interacts with SCF1 complex assembly	[106]
	Ank9	Perturbs Golgi-to-ER retrograde trafficking by binding COPB2 Binds SKP1 and CUL1 proteins, modulating UPR Binds SCF1 complex and transcription factors, modulating protein secretion	[107]
	Ank13	Interacts with RaDAR and downregulates multiple host genes, acting as a nucleomodulin Modulates cytoplasm gene expression Reprograms host cell transcription	[108]
Rickettsia spp.	rOmpB	Autotransporter Mediates adherence and invasion of non-phagocytic cells by binding Ku70 Binds H2B and facilitates infection in a tick cell line Mediates serum resistance by interacting with Factor H Promotes autophagy evasion (Prevents ubiquitination of bacterial surface proteins and subsequent recognition by autophagy receptors)	[109,110,111,112,115]
	PrsA	Mediates folding of secreted proteins Interacts with H2B and facilitates infection in a tick cell line	[112,116,117,118]
	Adr2	Interacts with vibronectin and mediates serum resistance May act as an adhesin	[119,120]
	Sca2	Mediates adherence and invasion of mammalian epithelial and endothelial cells Promotes actin filament nucleation and elongation to assemble actin tails Inhibits capping proteins’ activity	[121,122,123]
	APRc	Catalyzes in vitro processing of Sca5/OmpB and Sca0/OmpA Presents nonimmune Ig-binding activity & Targets host serum components Confers resistance to complement-mediated killing	[124,126]
Wolbachia spp.	WSP	Triggers innate immune system by interacting with TLR2 and TLR4 Delays apoptosis of human neutrophils Induces iNOS mRNA expression and NOS production Interacts with glycolytic enzymes and cytoskeleton proteins of Brugia malayi	[127,128,129,130,131]

Abbreviations: Abi-1: Abl-interactor 1, Ank200: 200 kDa ankyrin repeat protein, AnkA: ankyrin repeat domain-containing protein A, APRc: aspartic protease from Rickettsia conorii, Ats-1: Anaplasma translocated factor 1, COPB2: coatomer protein complex subunit beta 2, EF-1α: elongation factor-1 alpha, ER: endoplasmic reticulum, ERAD: ER-associated degradation, Etf-1: ehrlichial translocated factor 1, HDAC1: histone deacetylase 1, HSP70: 70-kDa heat shock protein, Ig: immunoglobulins, IL-8: interleukin 8, iNOS: nitric oxide producer, MnSod: manganese superoxide dismutase, MSP4: major surface protein 4, PrsA: parvulin-like peptidyl-prolylcis-transisomerase, RaDAR: RanGDP-ankyrin repeats, rOmpB: rickettsial outer membrane protein B, ROS: reactive oxygen species, Sca2: surface cell antigen 2, SHP-1: Src homology phosphatase-1, TGN: trans Golgi network, TLR2: Toll-like receptor 2, TNF-α: tumor necrosis factor alpha, TRP: tandem repeat protein, UMPK: uridine monophosphate kinase, UPR. unfolded protein response, WSP: Wolbachia surface protein.