Acknowledgement
We thank the members of the Liu laboratory for critical review of this
manuscript. We also thank Dr. Jiazhang Qiu from Jilin University for the
useful discussion on Legionella kinase effectors. Due to time
constraint as well as space limitation, we apologize to those colleagues
whose work was not discussed or cited in this paper. The work in our
group was financially supported by grants from National Key Research and
Development Program of China (2022YFA1304500), the Natural Science
Foundation of China (22174003 and 21974002), Peking University Medicine
Seed Fund for Interdisciplinary Research and the Fundamental Research
Funds for the Central Universities.
ORCID
Jie Jin https://orcid.org/0000-0001-8641-8843
Jiaqi Fu https://orcid.org/0000-0003-0081-6133
Xiaoyun Liu https://orcid.org/0000-0001-7083-5263
REFERENCES
Alonso, A., Bottini, N., Bruckner, S., Rahmouni, S., Williams, S.,
Schoenberger, S.P. et al. (2004) Lck dephosphorylation at Tyr-394 and
inhibition of T cell antigen receptor signaling by Yersiniaphosphatase YopH. Journal of Biological Chemistry, 279,4922-4928.https://doi.org/10.1074/jbc.M308978200.
Ashida, H., Kim, M. & Sasakawa, C. (2014) Exploitation of the host
ubiquitin system by human bacterial pathogens. Nature Reviews
Microbiology, 12 , 399-413.https://doi.org/10.1038/nrmicro3259.
Barz, C., Abahji, T.N., Trülzsch, K. & Heesemann, J. (2000) TheYersinia Ser/Thr protein kinase YpkA/YopO directly interacts with
the small GTPases RhoA and Rac-1. FEBS Letters, 482, 139-143.https://doi.org/10.1016/s0014-5793(00)02045-7.
Bette-Bobillo, P., Giro, P., Sainte-Marie, J. & Vidal, M. (1998)
Exoenzyme S from P. aeruginosa ADP-ribosylates rab4 and inhibits
transferrin recycling in SLO-permeabilized reticulocytes.Biochemical and Biophysical Research Communications, 244 ,
336-341.https://doi:.org/10.1006/bbrc.1998.8263.
Beyrakhova, K., Li, L., Xu, C., Gagarinova, A. & Cygler, M. (2018)Legionella pneumophila effector Lem4 is a membrane-associated
protein tyrosine phosphatase. Journal of Biological Chemistry,
293, 13044-13058.https://doi.org/10.1074/jbc.RA118.003845.
Black, D.S. & Bliska, J.B. (1997) Identification of p130Cas as a
substrate of Yersinia YopH (Yop51), a bacterial protein tyrosine
phosphatase that translocates into mammalian cells and targets focal
adhesions. The EMBO Journal, 16, 2730-2744.https://doi.org/10.1093/emboj/16.10.2730.
Black, M.H., Osinski, A., Park, G.J., Gradowski, M., Servage, K.A.,
Pawłowski, K. et al. (2021) A Legionella effector
ADP-ribosyltransferase inactivates glutamate dehydrogenase.Journal of Biological Chemistry, 296, 100301.https://doi.org/10.1016/j.jbc.2021.100301.
Bliska, J.B., Guan, K.L., Dixon, J.E. & Falkow, S. (1991) Tyrosine
phosphate hydrolysis of host proteins by an essential Yersiniavirulence determinant. Proceedings of the National Academy of
Sciences of the United States of America, 88, 1187-1191.https://doi.org/10.1073/pnas.88.4.1187.
Cassel, D. & Pfeuffer, T. (1978) Mechanism of cholera toxin action:
covalent modification of the guanyl nucleotide-binding protein of the
adenylate cyclase system. Proceedings of the National Academy of
Sciences of the United States of America, 75, 2669-2673.https://doi.org/10.1073/pnas.75.6.2669.
Chambers, K.A. & Scheck, R.A. (2020) Bacterial virulence mediated by
orthogonal post-translational modification. Nature Chemical
Biology, 16, 1043-1051.https://doi.org/10.1038/s41589-020-0638-2.
Choi, H.W., Brooking-Dixon, R., Neupane, S., Lee, C-J. Miao, E.A.,
Staats, H.F. et al. (2013) Salmonella typhimurium impedes innate
immunity with a mast-cell-suppressing protein tyrosine phosphatase,
SptP. Immunity, 39, 1108-1120.https://doi.org/10.1016/j.immuni.2013.11.009.
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M.L. Rehman, M., Walther,
T.C. et al. (2009) Lysine acetylation targets protein complexes and
co-regulates major cellular functions. Science, 325, 834-840.https://doi.org/10.1126/science.1175371.
Dukuzumuremyi, J.M., Rosqvist, R., Hallberg, B., Akerström, B.,
Wolf-Watz, H. & Schesser, K. (2000) The Yersinia protein kinase
A is a host factor inducible RhoA/Rac-binding virulence factor.Journal of Biological Chemistry, 275, 35281-35290.https://doi.org/10.1074/jbc.M003009200.
Fu, J., Zhou, M., Gritsenko, M.A., Nakayasu, E.S., Song, L. & Luo, Z.Q.
(2022) Legionella pneumophila modulates host energy metabolism by
ADP-ribosylation of ADP/ATP translocases. Elife, 11 , e73611.https://doi.org/10.7554/eLife.73611.
Galyov, E.E., Håkansson, S., Forsberg, A. & Wolf-Watz, H. (1993) A
secreted protein kinase of Yersinia pseudotuberculosis is an
indispensable virulence determinant. Nature, 361, 730-732.https://doi.org/10.1038/361730a0.
Gao, X., Wan, F., Mateo, K., Callegari, E., Wang, D., Deng, W. et al.
(2009) Bacterial effector binding to ribosomal protein s3 subverts NF-κB
function. PLoS Pathogens, 5, e1000708.https://doi.org/10.1371/journal.ppat.1000708.
Ge, J., Xu, H., Li, T., Zhou, Y., Zhang, Z., Li, S. et al. (2009) ALegionella type IV effector activates the NF-κB pathway by
phosphorylating the IκB family of inhibitors. Proceedings of the
National Academy of Sciences of the United States of America, 106,13725-13730.https://doi.org/10.1073/pnas.0907200106.
Gerke, C., Falkow, S. & Chien, Y-H. (2005) The adaptor molecules LAT
and SLP-76 are specifically targeted by Yersinia to inhibit T
cell activation. Journal of Experimental Medicine, 201, 361-371.https://doi.org/10.1084/jem.20041120.
Gonçalves, I.G., Simões, L.C. & Simões, M. (2021) Legionella
pneumophila . Trends in Microbiology, 29 , 860-861.https://doi.org/10.1016/j.tim.2021.04.005.
Grishin, A.M., Beyrakhova, K.A. & Cygler, M. (2015) Structural insight
into effector proteins of gram-negative bacterial pathogens that
modulate the phosphoproteome of their host. Protein Science, 24 ,
604-620.https://doi.org/10.1002/pro.2636.
Heggie, A., Cerny, O. & Holden, D.W. (2021) SteC and the intracellularSalmonella -induced F-actin meshwork. Cellular Microbiology,
23, e13315.https://doi.org/10.1111/cmi.13315.
Hemrajani, C., Berger, C.N., Robinson, K.S., Marchès, O., Mousnier, A.
& Frankel, G. (2010) NleH effectors interact with Bax inhibitor-1 to
block apoptosis during enteropathogenic Escherichia coliinfection. Proceedings of the National Academy of Sciences of the
United States of America, 107, 3129-3134.https://doi.org/10.1073/pnas.0911609106.
Hendriks, I.A., Larsen, S.C. & Nielsen, M.L. (2019) An advanced
strategy for comprehensive profiling of ADP-ribosylation sites using
mass spectrometry-based proteomics. Molecular & Cellular
Proteomics, 18 , 1010-1026.https://doi.org/10.1074/mcp.TIR119.001315.
Hervet, E., Charpentier, X., Vianney, A., Lazzaroni, J-C., Gilbert, C.,
Atlan, D. et al. (2011) Protein kinase LegK2 is a type IV secretion
system effector involved in endoplasmic reticulum recruitment and
intracellular replication of Legionella pneumophila .Infection and Immunity, 79, 1936-1950.https://doi.org/10.1128/IAI.00805-10.
Honjo, T., Nishizuka, Y. & Hayaishi, O. (1968) Diphtheria
toxin-dependent adenosine diphosphate ribosylation of aminoacyl
transferase II and inhibition of protein synthesis. Journal of
Biological Chemistry, 243, 3553-3555.https://doi.org/10.1016/S0021-9258(18)93347-8.
Hottiger, M.O., Hassa, P.O., Lüscher, B., Schüler, H. & Koch-Nolte, F.
(2010) Toward a unified nomenclature for mammalian
ADP-ribosyltransferases. Trends in Biochemical Sciences, 35 ,
208-219.https://doi.org/10.1016/j.tibs.2009.12.003.
Hou, Y., Zeng, H., Li, Z., Feng, N., Meng, F., Xu, Y. et al. (2023)
Structural mechanisms of calmodulin activation of Shigellaeffector OspC3 to ADP-riboxanate caspase-4/11 and block pyroptosis.Nature Structural & Molecular Biology, online ahead of print.https://doi.org/10.1038/s41594-022-00888-3.
Hubber, A. & Roy, C.R. (2010) Modulation of host cell function byLegionella pneumophila type IV effectors. Annual Review of
Cell and Developmental Biology, 26 , 261-283.https://doi.org/10.1146/annurev-cellbio-100109-104034.
Humphreys, D., Hume, P.J. & Koronakis, V. (2009) The Salmonellaeffector SptP dephosphorylates host AAA+ ATPase VCP to promote
development of its intracellular replicative niche. Cell Host &
Microbe, 5 , 225-233.https://doi.org/10.1016/j.chom.2009.01.010.
Huttlin, E.L., Jedrychowski, M.P., Elias, J.E., Goswami, T., Rad, R.,
Beausoleil, S.A. et al. (2010) A tissue-specific atlas of mouse protein
phosphorylation and expression. Cell, 143 , 1174-1189.https://doi.org/10.1016/j.cell.2010.12.001.
Imami, K., Bhavsar, A. P., Yu, H., Brown, N. F., Rogers, L. D., Finlay,
B. B. et al. (2013) Global impact of salmonella pathogenicity
Island 2-secreted effectors on the host phosphoproteome. Molecular
& Cellular Proteomics, 12, 1,632–1,643.https://doi.org/10.1074/mcp.M112.026161.
Isberg, R.R., O’Connor, T.J. & Heidtman, M. (2009) The Legionella
pneumophila replication vacuole: making a cosy niche inside host cells.Nature Reviews Microbiology, 7 , 13-24.https://doi.org/10.1038/nrmicro1967.
Jennings, E., Thurston, T.L.M. & Holden, D.W. (2017) SalmonellaSPI-2 type III secretion system effectors: molecular mechanisms and
physiological consequences. Cell Host & Microbe, 22 , 217-231.https://doi.org/10.1016/j.chom.2017.07.009.
Jennison, A.V. & Verma, N.K. (2004) Shigella flexneri infection:
pathogenesis and vaccine development. FEMS Microbiology Reviews,
28 , 43-58.https://doi.org/10.1016/j.femsre.2003.07.002.
Juris, S.J., Rudolph, A.E., Huddler, D., Orth, K. & Dixon, J.E. (2000)
A distinctive role for the Yersinia protein kinase: actin
binding, kinase activation, and cytoskeleton disruption.Proceedings of the National Academy of Sciences of the United
States of America, 97, 9431-9436.https://doi.org/10.1073/pnas.170281997.
Ke, Y., Tan, Y., Wei, N., Yang, F., Yang, H., Cao, S. et al. (2015)Yersinia protein kinase A phosphorylates vasodilator-stimulated
phosphoprotein to modify the host cytoskeleton. Cellular
Microbiology, 17, 473-485.https://doi.org/10.1111/cmi.12378.
Knodler, L.A. & Elfenbein, J.R. (2019) Salmonella enterica .Trends in Microbiology, 27 , 964-965.https://doi.org/10.1016/j.tim.2019.05.002.
Kubori, T., Lee, J., Kim, H., Yamazaki, K., Nishikawa, M., Kitao, T. et
al. (2022) Reversible modification of mitochondrial ADP/ATP translocases
by paired Legionella effector proteins. Proceedings of the
National Academy of Sciences of the United States of America, 119,e2122872119.https://doi.org/10.1073/pnas.2122872119.
Lee, P-C. & Machner, M.P. (2018) The Legionella effector kinase
LegK7 hijacks the host Hippo pathway to promote infection. Cell
Host & Microbe, 24, 429-438.e6.https://doi.org/10.1016/j.chom.2018.08.004.
Li, Z., Liu, W., Fu, J., Cheng, S., Xu, Y., Wang, Z. et al. (2021)
Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11.Nature, 599 , 290-295.https://doi.org/10.1038/s41586-021-04020-1.
Liu, Y., Zeng, H., Hou, Y., Li, Z., Li, L., Song, X. et al. (2022)
Calmodulin binding activates Chromobacterium CopC effector to
ADP-riboxanate host apoptotic caspases. mBio, 13, e0069022.https://doi.org/10.1128/mbio.00690-22.
Macek, B., Forchhammer, K., Hardouin, J., Weber-Ban, E., Grangeasse, C.
& Mijakovic, I. (2019) Protein post-translational modifications in
bacteria. Nature Reviews Microbiology, 17, 651-664.https://doi.org/10.1038/s41579-019-0243-0.
Mattock, E. & Blocker, A.J. (2017) How do the virulence factors ofShigella work together to cause disease? Frontiers in
Cellular Infection Microbiology, 7, 64.https://doi.org/10.3389/fcimb.2017.00064.
Michard, C., Sperandio, D., Baïlo, N., Pizarro-Cerdá, J., LeClaire, L.,
Chadeau-Argaud, E. et al. (2015) The Legionella kinase LegK2
targets the ARP2/3 complex to inhibit actin nucleation on phagosomes and
allow bacterial evasion of the late endocytic pathway. mBio, 6,e00354-15.https://doi.org/10.1128/mBio.00354-15.
Moss, S.M., Taylor, I.R., Ruggero, D., Gestwicki, J.E., Shokat, K.M. &
Mukherjee, S. (2019) A Legionella pneumophila kinase
phosphorylates the Hsp70 chaperone family to inhibit eukaryotic protein
synthesis. Cell Host & Microbe, 25, 454-462.e6.https://doi.org/10.1016/j.chom.2019.01.006.
Muthuramalingam, M., Whittier, S.K., Picking, W.L. & Picking, W.D.
(2021) The Shigella type III secretion system: an overview from
top to bottom. Microorganisms, 9 , 451.https://doi.org/10.3390/microorganisms9020451.
Navarro, L., Koller, A., Nordfelth, R., Wolf-Watz, H., Taylor, S. &
Dixon, J E. (2007) Identification of a molecular target for theYersinia protein kinase A. Molecular Cell, 26, 465-477.https://doi.org/10.1016/j.molcel.2007.04.025.
Nowak, K., Rosenthal, F., Karlberg, T., Bütepage, M., Thorsell, A.G.,
Dreier, B. et al. (2020) Engineering Af1521 improves ADP-ribose binding
and identification of ADP-ribosylated proteins. Nature
Communications, 11 , 5199.https://doi.org/10.1038/s41467-020-18981-w.
Odendall, C., Rolhion, N., Förster, A., Poh, J., Lamont, D., Liu, M. et
al. (2012) The salmonella kinase SteC targets the MAP kinase MEK
to regulate the host actin cytoskeleton. Cell Host & Microbe,
12, 657–668.https://doi.org/10.1016/j.chom.2012.09.011.
Olsen, J.V., Vermeulen, M., Santamaria, A., Kumar, C., Miller, A.L.,
Jensen, L.J. et al. (2010) Quantitative phosphoproteomics reveals
widespread full phosphorylation site occupancy during mitosis.Science Signaling, 3 , ra3.https://doi.org/10.1126/scisignal.2000475.
Palazzo, L., Mikoč, A. & Ahel, I. (2017) ADP-ribosylation: new facets
of an ancient modification. The FEBS Journal, 284 , 2932-2946.https://doi.org/10.1111/febs.14078.
Peng, T., Tao, X., Xia, Z., Hu, S., Xue, J., Zhu, Q. et al. (2022)
Pathogen hijacks programmed cell death signaling by arginine
ADPR-deacylization of caspases. Molecular Cell, 82 ,
1806-1820.https://doi.org/10.1016/j.molcel.2022.03.010.
Persson, C., Carballeira, N., Wolf-Watz, H. & Fällman, M. (1997) The
PTPase YopH inhibits uptake of Yersinia , tyrosine phosphorylation
of p130Cas and FAK, and the associated accumulation of these proteins in
peripheral focal adhesions. The EMBO Journal, 16, 2307-2318.https://doi.org/10.1093/emboj/16.9.2307.
Pinotsis, N. & Waksman, G. (2017) Structure of the WipA protein reveals
a novel tyrosine protein phosphatase effector from Legionella
pneumophila . Journal of Biological Chemistry, 292, 9240-9251.https://doi.org/10.1074/jbc.M117.781948.
Poh, J., Odendall, C., Spanos, A., Boyle, C., Liu, M., Freemont, P. et
al. (2008) SteC is a Salmonella kinase required for
SPI-2-dependent F-actin remodelling. Cellular Microbiology, 10 ,
20-30.https://doi.org/10.1111/j.1462-5822.2007.01010.x.
Pollock, G.L., Grishin, A.M., Giogha, C., Gan, J., Oates, C.V.,
McMillan, P.J. et al. (2022) Targeting of microvillus protein Eps8 by
the NleH effector kinases from enteropathogenic E. coli.Proceedings of the National Academy of Sciences of the United
States of America, 119, e2204332119.https://doi.org/10.1073/pnas.2204332119.
Prehna, G., Ivanov, M.I., Bliska, J.B. & Stebbins, C.E. (2006)Yersinia virulence depends on mimicry of host Rho-family
nucleotide dissociation inhibitors. Cell, 126, 869-880.https://doi.org/10.1016/j.cell.2006.06.056.
Prevost, M.S., Pinotsis, N., Dumoux, M., Hayward, R.D. & Waksman, G.
(2017) The Legionella effector WipB is a translocated Ser/Thr
phosphatase that targets the host lysosomal nutrient sensing machinery.Scientific Reports, 7, 9450.https://doi.org/10.1038/s41598-017-10249-6.
Qiu, J. & Luo, Z. (2017) Legionella and Coxiellaeffectors: strength in diversity and activity. Nature Reviews
Microbiology, 15, 591-605.https://doi.org/10.1038/nrmicro.2017.67.
Quaile, A.T., Stogios, P.J., Egorova, O., Evdokimova, E., Valleau, D.,
Nocek, B. et al. (2018) The Legionella pneumophila effector Ceg4
is a phosphotyrosine phosphatase that attenuates activation of
eukaryotic MAPK pathways. Journal of Biological Chemistry, 293,3307-3320.https://doi.org/10.1074/jbc.M117.812727.
Rogers, L.D., Brown, N.F., Fang, Y., Pelech, S. & Foster, L.J. (2011)
Phosphoproteomic analysis of Salmonella -infected cells identifies
key kinase regulators and SopB-dependent host phosphorylation events.Science Signaling, 4 , rs9.https://doi.org/10.1126/scisignal.2001668.
Rolán, H.G., Durand, E.A. & Mecsas, J. (2013) IdentifyingYersinia YopH-targeted signal transduction pathways that impair
neutrophil responses during in vivo murine infection. Cell Host &
Microbe, 14, 306-317.https://doi.org/10.1016/j.chom.2013.08.013.
Royan, S.V., Jones, R.M., Koutsouris, A., Roxas, J.L., Falzari, K.,
Weflen, A.W. et al. (2010) Enteropathogenic E. coli non-LEE
encoded effectors NleH1 and NleH2 attenuate NF-κB activation.Molecular Microbiology, 78, 1232-1245.https://doi.org/10.1111/j.1365-2958.2010.07400.x.
Schmutz, C., Ahrné, E., Kasper, C.A., Tschon, T., Sorg, I., Dreier, R.F.
et al. (2013) Systems-level overview of host protein phosphorylation
during Shigella flexneri infection revealed by phosphoproteomics.Molecular & Cellular Proteomics, 12 , 2952-2968.https://doi.org/10.1074/mcp.M113.029918.
Sreelatha, A., Nolan, C., Park, B.C., Pawłowski, K., Tomchick, D.R. &
Tagliabracci, V.S. (2020) A Legionella effector kinase is
activated by host inositol hexakisphosphate. Journal of Biological
Chemistry, 295, 6214-6224.https://doi.org/10.1074/jbc.RA120.013067.
Stebbins, C.E. & Galán, J.E. (2000) Modulation of host signaling by a
bacterial mimic: structure of the Salmonella effector SptP bound
to Rac1. Molecular Cell, 6, 1449-1460.https://doi.org/10.1016/s1097-2765(00)00141-6.
Vareechon, C., Zmina, S.E., Karmakar, M., Pearlman, E. & Rietsch, A.
(2017) Pseudomonas aeruginosa effector ExoS inhibits ROS
production in human neutrophils. Cell Host & Microbe, 21 ,
611-618.e5. https://doi.org/10.1016/j.chom.2017.04.001.
Villén, J., Beausoleil, S.A., Gerber, S.A. & Gygi, S.P. (2007)
Large-scale phosphorylation analysis of mouse liver. Proceedings
of the National Academy of Sciences of the United States of America,
104 , 1488-1493.https://doi.org/10.1073/pnas.0609836104.
Walch, P., Selkrig, J., Knodler, L.A., Rettel, M., Stein, F., Fernandez,
K. et al. (2021) Global mapping of Salmonella enterica-host
protein-protein interactions during infection. Cell Host &
Microbe, 29, 1316-1332.e12.https://doi.org/10.1016/j.chom.2021.06.004.
Wan, F., Weaver, A., Gao, X., Bern, M., Hardwidge, P.R. & Lenardo, M.J.
(2011) IKKβ phosphorylation regulates RPS3 nuclear translocation and
NF-κB function during infection with Escherichia coli strain
O157:H7. Nature Immunology, 12, 335-343.https://doi.org/10.1038/ni.2007.
Xu, G., Paige, J.S. & Jaffrey S.R. (2010) Global analysis of lysine
ubiquitination by ubiquitin remnant immunoaffinity profiling.Nature Biotechnology, 28, 868-873.https://doi.org/10.1038/nbt.1654.
Xu, Y., Cheng, S., Zeng, H., Zhou, P., Ma, Y., Li, L. et al. (2022) ARF
GTPases activate Salmonella effector SopF to ADP-ribosylate host
V-ATPase and inhibit endomembrane damage-induced autophagy. Nature
Structural & Molecular Biology, 29, 67-77.https://doi.org/10.1038/s41594-021-00710-6.
Xu, Y., Zhou, P., Cheng, S., Lu, Q., Nowak, K., Hopp, A.K. et al. (2019)
A bacterial effector reveals the V-ATPase-ATG16L1 axis that initiates
xenophagy. Cell, 178 , 552-566.e20.https://doi.org/10.1016/j.cell.2019.06.007.
Yan, F., Huang, C., Wang, X., Tan, J., Cheng, S., Wan, M. et al. (2020)
Threonine ADP-ribosylation of ubiquitin by a bacterial effector family
blocks host ubiquitination. Molecular Cell, 78 , 641-652.e9.https://doi.org10.1016/j.molcel.2020.03.016.
Zhang, Y., Fu, J., Liu, S., Wang, L., Qiu, J., van Schaik, E.J. et al.
(2022) Coxiella burnetii inhibits host immunity by a protein
phosphatase adapted from glycolysis. Proceedings of the National
Academy of Sciences of the United States of America, 119, e2110877119.https://doi.org/10.1073/pnas.2110877119.