Featured Publications
April, 2023
Molecular determinants for differential activation of the bile acid receptor from the pathogen Vibrio parahaemolyticus.
Angela J. Zou, Lisa Kinch, Suneeta Chimalapati, Nalleli Garcia, Diana R. Tomchick, and Kim Orth
Description
Pathogenic Vibrio parahaemolyticus differentially senses bile acids to induce pathogenesis. The bile acid taurodeoxycholate (TDC) activates the VtrB master transcription regulator of the Type III Secretion System (T3SS), whereas other bile acids such as chenodeoxycholate (CDC) do not. We present the crystal structure of the periplasmic VtrA/VtrB receptor bound to CDC, which competes for TDC binding. Using isothermal titration calorimetry, we observed most binding pocket mutants decreased affinity for bile acid. Notably, two mutants bound bile acids with a similar affinity as WT but were attenuated for TDC-induced T3SS activation. Collectively, these studies provide a molecular explanation for the selective pathogenic signaling by V. parahaemolyticus in response to bile acid.
March 2, 2023
Membrane-localized expression, production and assembly of Vibrio parahaemolyticus T3SS2 provides evidence for transertion.
Karan Gautam Kaval, Suneeta Chimalapati, Siegel Sara D., Nalleli Garcia, Jananee Jaishankar, Ankur B. Dalia & Kim Orth
Description
We provide evidence for transertion, the process of coupled transcription, translation and membrane insertion of the Type III Secretion System (T3SS) molecular machine by the bacterial pathogen Vibrio parahaemolyticus. We propose the pathogen accomplishes transertion by a two-step process initiated by the transmembrane co-component signaling system VtrA/VtrC, which turns on expression of a second membrane anchored transcription factor (VtrB) in response to bile acid. VtrB induces the localized expression and membrane assembly of the T3SS2 structural components. Transertion likely allows the efficient assembly of membrane-bound molecular complexes in response to extracellular signals.
August 1, 2022
Fic-mediated AMPylation tempers the unfolded protein response during physiological stress.
Casey AK, Gray HF, Chimalapati S, Hernandez G, Moehlman AT, Stewart N, Fields HA, Gulen B, Servage KA, Stefanius K, Blevins A, Evers BM, Krämer H, Orth K.
Description
We generated a conditional null allele of the AMPylating enzyme filamentation induced by cyclic-AMP (Fic) in mice and characterized the effect of Fic loss on the exocrine pancreas. We reveal Fic is required in differentiated tissue for the regulation of the unfolded protein response (UPR) during both physiological and pharmacological stresses. We also propose that cells with high regenerative capacity may not require this level of regulation, as new cells will bypass the need for long-term survival.
June 14, 2022
Co-component signal transduction systems: Fast-evolving virulence regulation cassettes discovered in enteric bacteria
Lisa N. Kinch, Qian Cong, Jananee Jaishankar, and Kim Orth
Description
We identified co-component signal transduction systems in enteric bacteria that are distantly related to the periplasmic bile acid receptor VtrA/VtrC from Vibrio parahaemolyticus. The newly identified co-component systems, which include the ToxR/ToxS master regulator of virulence, were identified using domain and operon organization combined with newly developed machine learning methods for structure prediction. The lipocalin-like fold adopted by all VtrC-like components suggests a regulatory role for sensing lipids in the virulence of enteric bacteria.
August 18, 2020
Vibrio deploys type 2 secreted lipase to esterify cholesterol with host fatty acids and mediate cell egress.
Suneeta Chimalapati, Marcela de Souza Santos, Alexander E Lafrance, Ann Ray, Wan-Ru Lee, Giomar Rivera-Cancel, Gonçalo Vale, Krzysztof Pawlowski, Matthew A Mitsche, Jeffrey G McDonald, Jen Liou, Kim Orth
Description
Using a combination of molecular tools, we found that VPA0226, a constitutively secreted lipase, is required for escape of V. parahaemolyticus from the host cells. This lipase must be delivered into the host cytoplasm where it preferentially uses fatty acids associated with innate immune response to esterify cholesterol. The activity weakens the plasma membrane and allows egress of the bacteria.
May 18, 2020
A distinct inhibitory mechanism of the V-ATPase by Vibrio VopQ revealed by cryo-EM.
Wei Peng, Amanda K Casey, Jessie Fernandez, Emily M Carpinone, Kelly A Servage, Zhe Chen, Yang Li, Diana R Tomchick, Vincent J Starai, Kim Orth
Description
The Vibrio parahaemolyticus T3SS effector VopQ targets host-cell V-ATPase, resulting in blockage of autophagic flux and neutralization of acidic compartments. Here, we report the cryo-EM structure of VopQ bound to the Vo subcomplex of the V-ATPase.
December 22, 2017
Fic-mediated deAMPylation is not dependent on homodimerization and rescues toxic AMPylation in flies.
Amanda K Casey, Andrew T Moehlman, Junmei Zhang, Kelly A Servage, Helmut Krämer, Kim Orth
Description
We show that excessive AMPylation by a constitutively active FicE247G mutant is lethal in Drosophila. This lethality is cell-autonomous, as directed expression of the mutant FicE247G to the fly eye does not kill the fly but rather results in a rough and reduced eye. Lethality and eye phenotypes are rescued by the deAMPylation activity of wild-type Fic.
July 5, 2016
Bile salt receptor complex activates a pathogenic type III secretion system
Peng Li, Giomar Rivera-Cancel, Lisa N Kinch, Dor Salomon, Diana R Tomchick, Nick V Grishin, Kim Orth
Description
We report the crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer. The VtrC fold adopts a β-barrel with a hydrophobic inner chamber. We present biophysical and mutational analysis to demonstrate the hydrophobic chamber binds bile salts and activates the T3SS2 virulence network.
January 9, 2009
AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling
Melanie L Yarbrough, Yan Li, Lisa N Kinch, Nick V Grishin, Haydn L Ball, Kim Orth
Description
We found the Vibrio parahaemolyticus type III effector VopS Fic domain covalently modifies a conserved threonine residue on Rho, Rac, and Cdc42 GTPases with adenosine 5′-monophosphate (AMP). The resulting AMPylation prevented the interaction of Rho GTPases with downstream effectors to inhibit actin assembly in the infected cell. This discovery expanded the repertoire of posttranslational modifications for molecular signaling and established a paradigm for catalysis by Fic domains.
AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling.
Yarbrough, M., Li, Y., Kinch, L.N., Grishin, N.V., Hall B.E., & Orth, K. January 2009 323 269-272A distinct inhibitory mechanism of the V-ATPase by Vibrio VopQ revealed by cryo-EM.
Peng W, Casey AK, Fernandez J, Carpinone EM, Servage KA, Chen Z, Li Y, Tomchick DR, Starai VJ, Orth K, 2020 May Nat. Struct. Mol. Biol.
Chimalapati S, de Souza Santos M, Lafrance AE, Ray A, Lee WR, Rivera-Cancel G, Vale G, Pawlowski K, Mitsche MA, McDonald JG, Liou J, Orth K,
2020 08
Elife
9
My winding trail while fulfilling my love for science and family.
Orth K 2018 Jul J. Biol. Chem. 27 293 10435-10437
Casey AK, Moehlman AT, Zhang J, Servage KA, Krämer H, Orth K
2018 Feb
J. Biol. Chem.
5
293
1550
Moehlman AT, Casey AK, Servage K, Orth K, Krämer H.
2018
17;7. pii: e38752. doi: 10.7554/eLife.38752. [Epub ahead of print]
Casey AK, Moehlman AT, Zhang J, Servage KA, Krämer H, Orth K
2017 12
J. Biol. Chem.
51
292
21193-21204
Bile salt receptor complex activates a pathogenic type III secretion system.
Li P, Rivera-Cancel G, Kinch LN, Salomon D, Tomchick DR, Grishin NV, Orth K 2016 Elife 5A Vibrio Effector Protein is an Inositol Phosphatase and Disrupts Host Cell Membrane Integrity
Broberg, C. A., Zhang, L.L., Gonzalez, H., Laskowski-Arce, M.A. & Orth, K September 2010 329 1660-1662Arp2/3 Independent Assembly of Actin by Vibrio Type III Effector VopL
Amy D.B. Liverman, Hui-Chun Cheng, Jennifer E. Trosky, Daisy W. Leung, Melanie L. Yarbrough, Dara L. Burdette, Michael K. Rosen and Kim Orth October 2007 104:43 17117-17122VopS Fic Domain uses direct transfer mechanism for AMPylation.
Luong, P., Kinch, L.N., Brautigam, C.A., Grishin, N.V., Tomchick, D.R. & Orth, K June 2010 285(26) 20155-20163Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways
Yi-Heng Hao,, Yong Wang, Dara Burdette, Sohini Mukherjee, Gladys Keitany, Elizabeth Goldsmith & Kim Orth January 2008 3(1) e1375Vibrio VopQ Induces PI3-Kinase Independent Autophagy and Antagonizes Phagocytosis.
Burdette, D., Seemann, J. & Orth, K August 2009 73 639-649
Kinch LN, Cong Q, Jaishankar J, Orth K,
2022 Jun
Proc Natl Acad Sci U S A
24
119
e2203176119
Stefanius K, Servage K, Orth K,
2021 Jan
Curr Opin Genet Dev
66
83-92
Manipulation of IRE1-Dependent MAPK Signaling by a Vibrio Agonist-Antagonist Effector Pair.
De Nisco NJ, Casey AK, Kanchwala M, Lafrance AE, Coskun FS, Kinch LN, Grishin NV, Xing C, Orth K, 2021 Feb mSystems 1 6
Vitetta ES, Cobb MH, Hobbs HH, Hooper L, Morrison SJ, Orth K, Pfeiffer J, Rosen MK, Takahashi JS, Wang T,
2021 Aug
Autophagy
1
Urinary prostaglandin E2 as a biomarker for recurrent UTI in postmenopausal women.
Ebrahimzadeh T, Kuprasertkul A, Neugent ML, Lutz KC, Fuentes JL, Gadhvi J, Khan F, Zhang C, Sharon BM, Orth K, Li Q, Zimmern PE, De Nisco NJ, 2021 07 Life Sci Alliance 7 4
Fernandez J, Lopez V, Kinch L, Pfeifer MA, Gray H, Garcia N, Grishin NV, Khang CH, Orth K,
2021 02
mBio
1
12
Servage KA, Stefanius K, Gray HF, Orth K,
2020 May
Sci Rep
1
10
7713
Bacterial adhesion inhibitor prevents infection in a rodent surgical incision model.
Huebinger RM, Do DH, Carlson DL, Yao X, Stones DH, De Souza Santos M, Vaz DP, Keen E, Wolf SE, Minei JP, Francis KP, Orth K, Krachler AM, 2020 Jan Virulence 1 11 695-706
Chimalapati S, Lafrance AE, Chen L, Orth K,
2020 Dec
Curr Protoc Microbiol
1
59
e131
Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex.
D'Souza RS, Lim JY, Turgut A, Servage K, Zhang J, Orth K, Sosale NG, Lazzara MJ, Allegood J, Casanova JE, 2020 Apr Elife 9
Stefanius K, Servage K, de Souza Santos M, Gray HF, Toombs JE, Chimalapati S, Kim MS, Malladi VS, Brekken R, Orth K,
2019 May
Elife
8
The Role of the Type III Secretion System in the Intracellular Lifestyle of Enteric Pathogens.
De Souza Santos M, Orth K, 2019 May Microbiol Spectr 3 7GCNA Preserves Genome Integrity and Fertility Across Species.
Bhargava V, Goldstein CD, Russell L, Xu L, Ahmed M, Li W, Casey A, Servage K, Kollipara R, Picciarelli Z, Kittler R, Yatsenko A, Carmell M, Orth K, Amatruda JF, Yanowitz JL, Buszczak M, 2019 Dec Dev. Cell
De Nisco NJ, Neugent M, Mull J, Chen L, Kuprasertkul A, de Souza Santos M, Palmer KL, Zimmern P, Orth K,
2019 Apr
J. Mol. Biol.
Yang H, de Souza Santos M, Lee J, Law HT, Chimalapati S, Verdu EF, Orth K, Vallance BA,
2019 12
mBio
6
10
High-resolution cryo-EM structures of the E. coli hemolysin ClyA oligomers.
Peng W, de Souza Santos M, Li Y, Tomchick DR, Orth K, 2019 PLoS ONE 5 14 e0213423Protein AMPylation by an Evolutionarily Conserved Pseudokinase.
Sreelatha A, Yee SS, Lopez VA, Park BC, Kinch LN, Pilch S, Servage KA, Zhang J, Jiou J, Karasiewicz-Urbanska M, Lobocka M, Grishin NV, Orth K, Kucharczyk R, Pawlowski K, Tomchick DR, Tagliabracci VS 2018 Oct Cell 3 175 809-821.e19
Moehlman AT, Casey AK, Servage K, Orth K, Krämer H
2018 Jul
Elife
7
Rise of a Cereal Killer: The Biology of Magnaporthe oryzae Biotrophic Growth.
Fernandez J, Orth K 2018 Jul Trends Microbiol. 7 26 582-597
Casey AK, Orth K
2018 Feb
Chem. Rev.
3
118
1199-1215
Natural Transformation in Vibrio parahaemolyticus: a Rapid Method To Create Genetic Deletions.
Chimalapati S, de Souza Santos M, Servage K, De Nisco NJ, Dalia AB, Orth K 2018 Aug J. Bacteriol. 15 200
De Nisco NJ, Rivera-Cancel G, Orth K
2018 01
MBio
1
9
Science Signaling Podcast for 16 May 2017: Vibrio rewires host cells.
De Nisco NJ, Orth K, VanHook AM 2017 May Sci Signal 479 10
De Nisco NJ, Kanchwala M, Li P, Fernandez J, Xing C, Orth K
2017 May
Sci Signal
479
10
de Souza Santos M, Salomon D, Orth K
2017 Jun
PLoS Pathog.
6
13
e1006438
Li P, Kinch LN, Ray A, Dalia AB, Cong Q, Nunan LM, Camilli A, Grishin NV, Salomon D, Orth K
2017 Jul
Appl. Environ. Microbiol.
13
83
Biochemical basis for activation of virulence genes by bile salts in Vibrio parahaemolyticus.
Rivera-Cancel G, Orth K 2017 Jan Gut Microbes 1-8Type VI secretion system MIX-effectors carry both antibacterial and anti-eukaryotic activities.
Ray A, Schwartz N, de Souza Santos M, Zhang J, Orth K, Salomon D 2017 11 EMBO Rep. 11 18 1978-1990
Huebinger RM, Stones DH, de Souza Santos M, Carlson DL, Song J, Vaz DP, Keen E, Wolf SE, Orth K, Krachler AM
2016 Dec
Sci Rep
6
39341
Proteomics Analysis Reveals Previously Uncharacterized Virulence Factors in Vibrio proteolyticus.
Ray A, Kinch LN, de Souza Santos M, Grishin NV, Orth K, Salomon D 2016 07 MBio 4 7
Salomon D, Orth K
2015 Mar
Curr. Biol.
7
25
R265-6
Vibrio effector protein VopQ inhibits fusion of V-ATPase-containing membranes.
Sreelatha A, Bennett TL, Carpinone EM, O'Brien KM, Jordan KD, Burdette DL, Orth K, Starai VJ 2015 Jan Proc. Natl. Acad. Sci. U.S.A. 1 112 100-5
de Souza Santos M, Orth K
2015 Feb
Cell. Microbiol.
2
17
164-73
Type VI Secretion System Toxins Horizontally Shared between Marine Bacteria.
Salomon D, Klimko JA, Trudgian DC, Kinch LN, Grishin NV, Mirzaei H, Orth K 2015 Aug PLoS Pathog. 8 11 e1005128H-NS regulates the Vibrio parahaemolyticus type VI secretion system 1.
Salomon D, Klimko JA, Orth K 2014 Sep Microbiology (Reading, Engl.) Pt 9 160 1867-73
de Souza Santos M, Orth K
2014 Sep
MBio
5
5
e01506-14
Ham H, Woolery AR, Tracy C, Stenesen D, Krämer H, Orth K
2014 Nov
J. Biol. Chem.
AMPylation of Rho GTPases subverts multiple host signaling processes.
Woolery AR, Yu X, LaBaer J, Orth K 2014 Nov J. Biol. Chem. 47 289 32977-88
Salomon D, Kinch LN, Trudgian DC, Guo X, Klimko JA, Grishin NV, Mirzaei H, Orth K
2014 Jun
Proc. Natl. Acad. Sci. U.S.A.
25
111
9271-6
Lewallen DM, Sreelatha A, Dharmarajan V, Madoux F, Chase P, Griffin PR, Orth K, Hodder P, Thompson PR
2014 Feb
ACS Chem. Biol.
2
9
433-42
Calder T, de Souza Santos M, Attah V, Klimko J, Fernandez J, Salomon D, Krachler AM, Orth K
2014 Dec
FEMS Microbiol. Lett.
2
361
107-14
Calder T, Kinch LN, Fernandez J, Salomon D, Grishin NV, Orth K
2014
PLoS ONE
8
9
e104387
What pathogens have taught us about posttranslational modifications.
Salomon D, Orth K 2013 Sep Cell Host Microbe 3 14 269-79
Altura MA, Heath-Heckman EA, Gillette A, Kremer N, Krachler AM, Brennan C, Ruby EG, Orth K, McFall-Ngai MJ
2013 Nov
Environ. Microbiol.
11
15
2937-50
Targeting the bacteria-host interface: strategies in anti-adhesion therapy.
Krachler AM, Orth K 2013 May Virulence 4 4 284-94
Sreelatha A, Bennett TL, Zheng H, Jiang QX, Orth K, Starai VJ
2013 Jul
Proc. Natl. Acad. Sci. U.S.A.
28
110
11559-64
Orth K
2013 Jul
Trends Biochem. Sci.
7
38
331-2
Alto NM, Orth K
2012 Sep
Cold Spring Harb Perspect Biol
9
4
a006114
Type III effector VopC mediates invasion for Vibrio species.
Zhang L, Krachler AM, Broberg CA, Li Y, Mirzaei H, Gilpin CJ, Orth K 2012 May Cell Rep 5 1 453-60
Krachler AM, Ham H, Orth K
2012 Jan-Feb
Virulence
1
3
68-71
De-AMPylation unmasked: modulation of host membrane trafficking.
Ham H, Orth K 2011 Oct Sci Signal 194 4 pe42
Krachler AM, Orth K
2011 Nov
J. Biol. Chem.
45
286
38939-47
Grammel M, Luong P, Orth K, Hang HC
2011 Nov
J. Am. Chem. Soc.
43
133
17103-5
Vibrio parahaemolyticus cell biology and pathogenicity determinants.
Broberg CA, Calder TJ, Orth K 2011 Nov Microbes Infect. 12-13 13 992-1001
Ham H, Sreelatha A, Orth K
2011 Jul
Nat. Rev. Microbiol.
9
9
635-46
Krachler AM, Ham H, Orth K
2011 Jul
Proc. Natl. Acad. Sci. U.S.A.
28
108
11614-9
Krachler AM, Woolery AR, Orth K
2011 Dec
J. Cell Biol.
7
195
1083-92
Tipping the balance by manipulating post-translational modifications.
Broberg CA, Orth K 2010 Feb Curr. Opin. Microbiol. 1 13 34-40
Woolery AR, Luong P, Broberg CA, Orth K
2010
Front Microbiol
1
113
Fido, a novel AMPylation domain common to fic, doc, and AvrB.
Kinch LN, Yarbrough ML, Orth K, Grishin NV 2009 Jun PLoS ONE 6 4 e5818
Yarbrough ML, Orth K
2009 Jun
Nat. Chem. Biol.
6
5
378-9
AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling.
Yarbrough ML, Li Y, Kinch LN, Grishin NV, Ball HL, Orth K 2009 Jan Science 5911 323 269-72
Mukherjee S, Orth K
2008 Nov
Science
5904
322
1062-3
In vitro activation of the IkappaB kinase complex by human T-cell leukemia virus type-1 Tax.
Mukherjee S, Negi VS, Keitany G, Tanaka Y, Orth K 2008 May J. Biol. Chem. 22 283 15127-33
Trosky JE, Liverman AD, Orth K
2008 Mar
Cell. Microbiol.
3
10
557-65
Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways.
Hao YH, Wang Y, Burdette D, Mukherjee S, Keitany G, Goldsmith E, Orth K 2008 Jan PLoS ONE 1 3 e1375Acanthamoeba castellanii promotes the survival of Vibrio parahaemolyticus.
Laskowski-Arce MA, Orth K 2008 Dec Appl. Environ. Microbiol. 23 74 7183-8
Burdette DL, Yarbrough ML, Orvedahl A, Gilpin CJ, Orth K
2008 Aug
Proc. Natl. Acad. Sci. U.S.A.
34
105
12497-502
In vitro signaling by MAPK and NFkappaB pathways inhibited by Yersinia YopJ.
Mukherjee S, Orth K 2008 Meth. Enzymol. 438 343-53
Burdette, D., Yarbrough, M., Orvedahl, A., Gilpin, C. & Orth, K.
2008
105
12497-12502
Arp2/3-independent assembly of actin by Vibrio type III effector VopL.
Liverman AD, Cheng HC, Trosky JE, Leung DW, Yarbrough ML, Burdette DL, Rosen MK, Orth K 2007 Oct Proc. Natl. Acad. Sci. U.S.A. 43 104 17117-22The elusive activity of the Yersinia protein kinase A kinase domain is revealed.
Laskowski-Arce MA, Orth K 2007 Oct Trends Microbiol. 10 15 437-40VopA inhibits ATP binding by acetylating the catalytic loop of MAPK kinases.
Trosky JE, Li Y, Mukherjee S, Keitany G, Ball H, Orth K 2007 Nov J. Biol. Chem. 47 282 34299-305
Mukherjee S, Hao YH, Orth K
2007 May
Trends Biochem. Sci.
5
32
210-6
Chosed R, Tomchick DR, Brautigam CA, Mukherjee S, Negi VS, Machius M, Orth K
2007 Mar
J. Biol. Chem.
9
282
6773-82
Chosed R, Mukherjee S, Lois LM, Orth K
2006 Sep
Biochem. J.
3
398
521-9
Fehr D, Casanova C, Liverman A, Blazkova H, Orth K, Dobbelaere D, Frey J, Burr SE
2006 Sep
Microbiology (Reading, Engl.)
Pt 9
152
2809-18
Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation.
Mukherjee S, Keitany G, Li Y, Wang Y, Ball HL, Goldsmith EJ, Orth K 2006 May Science 5777 312 1211-4Yersinia YopJ Acetylates and Inhibits Kinase Activation by Preventing Phosphorylation
Mukherjee, S. Kietany, G., Li, Y Wang, Y., Hall B.E., Goldsmith, E & Orth, K 2006 312 1211-1214Publications by Year
2023
- Zou AJ, Kinch L, Chimalapati S, Garcia N, Tomchick DR, Orth K. Molecular determinants for differential activation of the bile acid receptor from the pathogen Vibrio parahaemolyticus. J Biol Chem. 2023 Apr;299(4):104591. doi: 10.1016/j.jbc.2023.104591.
- Kaval KG, Chimalapati S, Siegel SD, Garcia N, Jaishankar J, Dalia AB, Orth K. Membrane-localized expression, production and assembly of Vibrio parahaemolyticus T3SS2 provides evidence for transertion. Nat Commun. 2023 Mar 2;14(1):1178. doi: 10.1038/s41467-023-36762-z.
2022
- Lafrance AE, Chimalapati S, Garcia Rodriguez N, Kinch LN, Kaval KG, Orth K. Enzymatic Specificity of Conserved Rho GTPase Deamidases Promotes Invasion of Vibrio parahaemolyticus at the Expense of Infection. mBio. 2022 Aug 30;13(4):e0162922.
- Casey AK, Gray HF, Chimalapati S, Hernandez G, Moehlman AT, Stewart N, Fields HA, Gulen B, Servage KA, Stefanius K, Blevins A, Evers BM, Krämer H, Orth K. Fic-mediated AMPylation tempers the unfolded protein response during physiological stress. Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2208317119. doi: 10.1073/pnas.2208317119.
- Kinch LN, Cong Q, Jaishankar J, Orth K. Co-component signal transduction systems: Fast-evolving virulence regulation cassettes discovered in enteric bacteria. Proc Natl Acad Sci U S A. 2022 Jun 14;119(24):e2203176119. doi: 10.1073/pnas.2203176119.
2021
- Ebrahimzadeh T, Kuprasertkul A, Neugent ML, Lutz KC, Fuentes JL, Gadhvi J, Khan F, Zhang C, Sharon BM, Orth K, Li Q, Zimmern PE, De Nisco NJ. Urinary prostaglandin E2 as a biomarker for recurrent UTI in postmenopausal women. Life Sci Alliance. 2021 May 6;4(7):e202000948. doi: 10.26508/lsa.202000948.
- De Nisco, N. J., Casey, A. K., Kanchwala, M., Lafrance, A. E., Coskun, F. S., Kinch, L. N., . . . & Orth, K. (2021). Manipulation of ire1-dependent mapk signaling by a vibrio agonist-antagonist effector pair. MSystems, 6(1). doi:10.1128/msystems.00872-20
- Fernandez, J., Lopez, V., Kinch, L., Pfeifer, M. A., Gray, H., Garcia, N., . . . & Orth, K. (2021). Role of two metacaspases in development and pathogenicity of the Rice Blast fungus Magnaporthe oryzae. MBio, 12(1). doi:10.1128/mbio.03471-20
- Stefanius, K., Servage, K., & Orth, K. (2021). Exosomes in cancer development. Current Opinion in Genetics & Development, 66, 83-92. doi:10.1016/j.gde.2020.12.018
2020
- Chimalapati, S., de Souza Santos, M.*, Lafrance, A., Ray, A., Lee, W-R., Rivera-Cancel, G., Vale, G., Pawłowski, K., Mitsche, M., McDonald, J.G. , Liou, J. & Orth, K. Vibrio deploys a Type 2 secreted lipase to esterify cholesterol with host fatty acids and mediate T3SS2-mediated cell egress. eLife, 9:e58057.
- Peng, W., Fernandez, J., Casey, A. K., Kinch, L. N., Tomchick, D. R., & Orth, K. (2020). Structures of an intact yeast v-atpase alone and in complex with bacterial effector vopq. doi:10.1101/2020.07.16.207225
- Peng, W., Casey, A. K., Fernandez, J., Carpinone, E. M., Servage, K. A., Chen, Z., Li, Y., Tomchick, D. R., Starai, V. J., & Orth, K. (2020). A distinct inhibitory mechanism of the V-ATPase by Vibrio VopQ revealed by cryo-EM. Nature structural & molecular biology, 10.1038/s41594-020-0429-1. Advance online publication.
- Servage, K. A., Stefanius, K., Gray, H. F., & Orth, K. (2020). Proteomic Profiling of Small Extracellular Vesicles Secreted by Human Pancreatic Cancer Cells Implicated in Cellular Transformation. Scientific reports, 10(1), 7713.
2019
- Yang, H.*, de Souza Santos, M.*, Lee, J., Law, H.T., Chimalapati, S., Verdu, E.F., Orth, K. #, and Vallance, B.A.# A novel mouse model of enteric Vibrio parahaemolyticus infection reveals the T3SS2effector VopC plays a key role in tissue invasion and gastroenteritis. (2019) *contributed equally, #co-corresponding. mBio 17;10(6). pii: e02608-19. doi: 10.1128/mBio.02608-19.
- Stefanius, K., Servage, K., de Souza Santos, M., Chimalapati, S., Gray, H., Kim, M., Brekken, R. & Orth, K. Pancreatic Cancer Cell Exosomes Initiate Cellular Transformation and Tumor formation. eLife, (2018) May 28;8. pii: e40226. doi: 10.7554/eLife.40226.
- Peng, W., de Souza Santos, M., Tomchick, D. & Orth, K. Assembly mechanism of the E. coli hemolysin ClyA pore complexes. PLoS ONE (2019) May 2;14(5):e0213423. doi: 10.1371/journal.pone.0213423.
- De Nisco, N., Neugent, M., Mull, J., Chen, L., Kuprasertkul, A., de Souza Santos, M., Palmer, K., Zimmern, P. & Orth, K. Direct detection of tissue-resident bacteria and chronic inflammation in the bladder wall of postmenopausal women with recurrent urinary tract infection. Journal of Molecular Biology (2019) Apr 17. pii: S0022-2836(19)30202-5.
2018
- Sreelatha, A., Yee, S.S., Lopez, V.A., Park, B.C., Kinch, L., Pilch, S., Servage, K.A., Zhang, J., Jiou, J., Karasiewicz, M., M?obocka, M., Grishin, N., Orth, K, Kucharczyk, R., Paw?owski, K., Tomchick, D. R., and Tagliabracci. V.S. Protein AMPylation by an evolutionarily conserved pseudokinase. Cell. (2018) 175(3):809-821
- Moehlman, A.T., Casey, A.K., Servage, K., Orth, K* & Krämer, H.* Regulation of the Unfolded Protein Response by BiP AMPylation protects photoreceptors from light-dependent degeneration. eLife. (2018) Jul 17:7. Pii:e38752. doi:10.7554/eLife.38752. PMID: 30015618.
- Orth, K. My winding trail while fulfilling my love for science and family. J Biol Chem.. (2018) pii: jbc.AW118.003225. doi: 10.1074/jbc.AW118.003225
- Chimalapati,S., de Souza Santos, M., Servage, K., De Nisco, N.J., Dalia, A.B. & Orth, K. Natural transformation of Vibrio parahaemolyticus: A rapid method to create genetic deletions. J. Bac. 2018 Jul 10;200(15). pii: e00032-18. doi: 10.1128/JB.00032-18
- Fernandez, J. & Orth, K. Rise of a Cereal Killer: The Biology of Magnaporthe oryzae Biotrophic Growth. Trends in Microbiology (2018)
- De Nisco, N.J., Rivera-Cancel, G. & Orth, K. The biochemistry of sensing: How enteric pathogens regulate type III secretion in response to environmental and host cues. mBio. (2018) vol. 9 no. 1 e02122-17
2017
- Ray, A., Schwartz, N., de Souza Santos, M., Zhang, J. Orth, K & Salomon, D. Type VI secretion system MIX-effectors are targeting at both Bacterial and eukaryotic neighbors. EMBO Report. (2017) e201744226
- Casey, A.K. & Orth, K. Enzymes involved in AMPylation and deAMPylation. Chemical Reviews. (2017) Aug 18. doi: 10.1021/acs.chemrev.7b00145.
- Cancel-Rivera, G. & Orth, K. Biochemical basis for activation of virulence genes by bile salts in Vibrio parahaemolyticus. Gut Microbes.. (2017) Jan 27:0. doi: 10.1080/19490976.2017.1287655
- Casey, A.K., Moelman, A., Zhang, J., Servage, K., Kramer, H. & Orth, K. Fic-mediated deAMPylation of BiP is not dependent on homo-dimerization and rescues toxic AMPylation in flies. J Biol Chem. (2017) 292 (51) pg 21193-21204)
- de Souza Santos, M., Salomon, D. & Orth, K. T3SS effector VopL inhibits the host ROS response, promoting the intracellular survival of Vibrio parahaemolyticus. PLoS Pathog (2017) 13(6): e1006438. doi: 10.1371/journal.ppat.100643
- Li,P., Salomon, D., Kinch, L.N., Ray, A., Dalia, A.B., Cong, Q., Ninan, L., Camilli, A., Grishin, N.V. & Orth, K. Acute Hepatopancreatic Necrosis Disease (AHPND) causing Vibrio parahaemolyticus contains a virulent Type VI Secretion System (T6SS) with anti-bacterial activities. Appl Environ Microbiol. (2017) Apr 21. pii: AEM.00737-17. doi: 10.1128/AEM.00737-17
- De Nisco, N.J., Kanchwala, M., Li, P., Fernandez, J., Xing, C. & Orth, K. Cytotoxic Vibrio T3SS1 Rewires Host Gene Expression to Subvert Cell Death Signaling and Activate Cell Survival Networks. Sci Signal (2017) May 16;10(479). pii: eaal4501. doi: 10.1126/scisignal.aal4501
- De Nisco, N.J., Orth, K. & VanHook, A.M., Signaling Science Podcast: Vibrio Rewires host cells. Sci Signal. 2017 May 16;10(479). pii: eaan5621. doi: 10.1126/scisignal.aan5621
2016
- Huebinger, R.M., Stones, D.H., de Souza Santos, M., Carlson, D.L., Song, J., Vaz, D.P., Keen, E., Wolf, S.E., Orth, K. & Krachler, A. M. Targeting bacterial adherence inhibits multidrug-resistant Pseudomonas aeruginosa infection following burn injury. (2016) Scientific Reports Dec 20;6:39341. doi: 10.1038/srep39341
- Li, P., Rivera-Cancel, G., Kinch, L.N., Salomon, D., Tomchick, D.R., Grishin, N.V. & Orth, K. Bile Salt Receptor Complex Activates a Pathogenic Type III Secretion System (2016) eLife 5:e15718.
- Ray, A., Kinch, L.N., , de Souza Santos, M., Grishin, N.V., Orth, K. & Salomon, D. Proteomics analysis reveals previously uncharacterized virulence factors in Vibrio proteolyticus (2016) mBio 7(4):e01077-16. doi:10.1128/mBio.01077-16.
2015
- Salomon, D., Klimko, J.A., Trudgian, D.C., Kinch, L.N., Grishin, N.V., Mirzaei, H & Orth, K. Type VI secretion system toxins horizontally shared between marine bacteria (2015) PLoS Pathogen Aug 25;11(8):e1005128. PMID 26305100.
- Sreelatha, A., Bennett, T.L., Carpinone, E.M., O’Brien, K.M., Jordan, K.D., Burdette, D.L., Orth, K, & Starai, V.J. The Vibrio effector protein, VopQ, inhibits fusion of V-ATPase containing membranes. (2015) PNAS 112(1):100-5 PMID:25453092.
2014
- Ham H., Woolery A.R., Tracy C., Stenesen D., Krämer H. & Orth, K. Unfolded protein response-regulated dFic reversibly AMPylates BiP during ER homeostasis. (2014) JBC 289(52):36059-69 PMID: 25395623.
- Calder, T., Santos, M.S., Attah, V., Klimko, J., Frernandez, J., Salomon, D., Krachler, A.M., & Orth, K. Structural and regulatory mutations in Vibrio parahaemolyticus type III secretion systems display variable effects on virulence. (2014) FEMS 361(2):107-14. PMID 25288215.
- Woolery, A.R., Yu, X., LaBaer, J.& Orth, K. AMPylation of Rho GTPases subverts multiple host signaling processes. (2014) JBC 289(47):32977-88. PMID 25301945.
- de Souza Santos, M.S.. & Orth, K. Intracellular Vibrio parahaemolyticus Escapes the Vacuole and Establishes a Replicative Niche in the Cytosol of Epithelial Cells. (2014) mBio 9;5(5):e01506-14.
- Yu, X., Woolery, A.R., Luong, P., Hao, Y.H., Grammel, M., Westcott, N., Park, J., Wang, J., Bian, X., Demirkan, G., Hang, H.C., Orth, K. & LaBaer, J. Click chemistry-based detection of global pathogen-host AMPylation on self-assembled human protein microarrays. (2014) Mol & Cell Proteomics 13(11):3164-76. PMID 25073739.
- Calder, T., Kinch, L.N., Fernandez, J., Salomon, D., Grishin, N.V., & Orth, K. Vibrio type III effector VPA1380 is related to the cysteine protease domain of large bacterial toxin PLoS ONE 6;9(8):e104387 PMID 25099122.
- Salomon, D., Klimko, & Orth, K. H-NS regulates the Vibrio parahaemolyticus type VI secretion system 1. (2014) Microbiology 160(Pt9):1867-73. PMID:24987102.
- Salomon, D., Kinch, L.N., Trudgian, D.C., Guo, X., Klimko, J.A., Grishin, N.V., Mirzaei, H & Orth, K. Marker for type VI secretion system effectors. PNAS USA (2014) 111(25):9271-6 PMID 24927539.
- Lewallen,D.M., Sreelatha, A., Dharmarajan, V., Madoux, F., Chase,, F. ,Griffin, P.R., Orth, K., Hoddler, P. & Thompson, P.R. Inhibiting AMPylation: a novel screen to identify the first small molecule inhibitors of protein AMPylation. ACS Chem Biol (2014) 9(2): 433-432 PMC3944102.
2013
- Sreelatha, A., Orth, K., & Starai, V.J. The pore-forming bacterial effector, VopQ, halts autophagic turnover. Autophagy (2013) 9(12): 2169-70. PMID:24145145.
- Salomon D., Guo, Y., Kinch, L.N., Grishin, N.V., Mirzaei, H. & Orth, K. Effectors of animal and plant pathogens use a common domain to bind host phosphoinositides. Nature Communications (2013) 4:2973. Doi:10.1038/n,comms3973.
- Hawley, C.A., Watson, C., Orth, K. & Krachler, A-M. High-affinity binding of bacterial fibronectin-binding proteins to host cells inhibits critical steps in wound healing. PloS ONE (2013) 8.11:e81216.
- Sreelatha, A., Bennett,T. L., Zheng, H., Jiang, Q.X., Orth, K.*, & Starai, V.J.* Vibrio VopQ forms a gated outward rectifying channel that disrupts host ion homeostasis. PNAS USA (2013) 110(28):11559-64.
- Altura, M.A., Heath-Heckman, E.A., Gillette, A. Kremer, A-M, Krachler, A.M. Brennean, c., Ruby, E.G., Orth, K., McFall-Ngai, M.J. (2013) The first engagement of partners in the Euprymna scolopes-Vibrio fischeri symbiosis is a two-step process initiated by a few environmental symbiont cells. Environ Microbiol. (2013) Jun 11. doi: 10.1111/1462-2920.12179 (Epub ahead of print).
- Salomon, D. & Orth, K. What Pathogens Have Taught Us About Posttranslational Modifications (2013) Cell Host Pathogens 14:3 269-279.
- Krachler, A-M. & Orth, K. Made to stick: Anti-adhesion therapy for bacterial infections as an alternative to conventional antimicrobials. (2013) Microbe 8:286-290.
- Krachler, A-M. & Orth, K. Targeting the bacteria-host interface: strategies in anti-adhesion therapy (2013) Virulence 4(4): 284-94.
- Salomon, D. & Orth, K. Lost after translation: post-translational modifications by bacterial type III effectors. (2013) Current Opinions in Microbiology 6(2):213-20.
- Zhang, L.L & Orth, K. Virulence Determinants for Vibrio parahaemolyticus Infection. Current Opinions in Microbiology (2013) 16(1):70-7.
- Salomon, D., Gonzalez, H., Updegraff, B.L. & Orth, K. Vibrio parahaemolyticus Type VI Secretion System 1 is Activated in Marine Conditions to Target Bacteria, and is Differentially Regulated from System 2. PLoS ONE (2013) 8:4 e61086.
2012
- Ham, H. & Orth, K. The Role of Type III Secretion System 2 in Vibrio parahaemolyticus Pathogenicity. J Microbiol. (2012) Oct;50(5):719-25. PMID:23124738[PubMed - in process]
- Krachler AM & Orth, K. In vitro characterization of Multivalent Adhesion Molecule 7-based inhibition of multidrug-resistant bacteria isolated from wounded military personnel. Virulence (2012) (In Press)
- Alto, N.M. & Orth, K. Subversion of cell signaling by pathogens. In Signal Transduction Textbook. Cold Spring Harbor Press (2012).
- Zhang, L.L, Krachler, A-M, Broberg, CA, Li, Y, Mirzaei, H, Gilpin, CJ & Orth, K. Type III effector VopC mediates invasion for Vibrio species. Cell Reports (2012) 1(5): 453-460.
- Rahman, M., Ham, H., Liu, X., Sugiura, Y., Orth, K. and Krämer, H. Visual neurotransmission in Drosophila requires expression of dFic in glial capitate projections. Nature Neuroscience (2012) Apr 29. doi: 10.1038/nn.3102. [Epub ahead of print] PMID:22544313.
- Krachler, A-M, Ham, H. & Orth, K. Turnabout is fair play: Use of the bacterial Multivalent Adhesion Molecule 7 as an antimicrobial agent. Virulence (2012) 1;3(1).
2011
- Krachler AM & Orth, K. Functional characterization of the interaction between bacterial adhesin multivalent adhesion molecule 7 (MAM7) protein and its host cell ligands. J Biol Chem. (2011) Nov 11;286(45):38939-47.
- Grammel M, Luong P, Orth, K, Hang HC. A chemical reporter for protein AMPylation. J Am Chem Soc. (2011) Nov 2;133(43):17103-5.
- Krachler, A-M, Woolery, A.R. & Orth, K. Host-pathogen interactions: Manipulation of kinase signaling by bacterial pathogens. (2011) J. Cell Biol 195(7):1083-92.
- Krachler AM, Ham H, Orth, K. The outer membrane adhesion factor MAM7 initiates host cell binding during infection with Gram-negative pathogens. (2011) Proc Natl Acad Sci USA. Epub June 2011.
- Ham H., Sreelatha, A. & Orth, K. (2011) Manipulation of Host Membranes by Bacterial Effectors. Nature Reviews Microbiology 9(9):635-46.
- Broberg, CA, Calder, TJ, & Orth, K. Vibrio parahaemolyticus cell biology and pathogenicity determinants. Microbes Infect. 2011 Nov;13(12-13):992-1001. Epub 2011 Jul 7.
- Hao YH, Chuang T, Ball HL, Luong P, Li Y, Flores-Saaib RD, Orth, K. Characterization of a rabbit polyclonal antibody against threonine-AMPylation. (2011) J Biotechnol. 151(3):251-4.
- Li Y, Al-Eryani R, Yerbrough ML, Orth, K, Ball HL. Characterization of AMPylation on threonine, serine, and tyrosine using mass spectrometry. (2011) J Am Soc Mass Spectrom. 22(4):752-61.
- Krachler AM, Orth, K. Black Spot, Black Death, Black Pearl: Tales of Bacterial Effectors. Chapter in Avancées et nouvelles technologies en Toxinologie – Advances and new technologies in Toxinology (SFET, ed.). ISSN 1760 – 6004.
2010
- Broberg CA, Zhang L, Gonzalez H, Laskowski-Arce MA, Orth, K. A Vibrio effector protein is an inositol phosphatase and disrupts host cell membrane integrity. (2010) Science. 329(5999):1660-2.
- Luong P, Kinch LN, Brautigam CA, Grishin NV, Tomchick DR, Orth, K. Kinetic and structural insights into the mechanism of AMPylation by VopS Fic domain. (2010) J Biol Chem. 285(26):20155-63.
- Broberg CA, Orth, K. Tipping the balance by manipulating post-translational modifications. (2010) Curr Opin Microbiol. 13(1):34-40.
- Woolery AR, Luong P, Broberg CA, Orth, K. AMPylation: Something Old is New Again. (2010) Front Microbiol. 1:113.
2009
- Burdette DL, Seemann J, Orth, K. Vibrio VopQ induces PI3-kinase-independent autophagy and antagonizes phagocytosis. (2009) Mol Microbiol. 73(4):639-49.
- Kinch LN, Yarbrough ML, Orth, K, Grishin NV. Fido, a novel AMPylation domain common to fic, doc, and AvrB. (2009) PLoS One. 4(6):e5818.
- Yarbrough ML, Orth, K. AMPylation is a new post-translational modification. (2009) Nat Chem Biol. 5(6):378-9.
- Yarbrough ML, Li Y, Kinch LN, Grishin NV, Ball HL, Orth, K. AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling. (2009) Science. 323(5911):269-72.
- Burdette DL, Yarbrough ML, Orth, K. Not without a cause: Vibrio parahaemolyticus induces acute autophagy and cell death. (2009) Autophagy. 5(1):100-2.
2008
- Mukherjee S, Orth, K. Microbiology. A protein pupylation paradigm. (2008) Science. 322(5904):1062-3.
- Laskowski-Arce MA, Orth, K. Acanthamoeba castellanii promotes the survival of Vibrio parahaemolyticus. (2008) Appl Environ Microbiol. 74(23):7183-8.
- Burdette L, Yarbrough ML, Orvedahl A, Gilpin CJ, Orth, K. Vibrio parahaemolyticus orchestrates a multifaceted host cell infection by induction of autophagy, cell rounding, and then cell lysis. (2008) Proc Natl Acad Sci USA. 105(34):12497-502.
- Mukherjee S, Orth, K. in vitro signaling by MAPK and NFkappaB pathways inhibited by Yersinia YopJ. (2008) Methods Enzymol. 438:343-53.
- Le Negrate G, Faustin B, Welsh K, Loeffler M, Krajewska M, Hasegawa P, Mukherjee S, Orth, K, Krajewski S, Godzik A, Guiney DG, Reed JC. Salmonella secreted factor L deubiquitinase of Salmonella typhimurium inhibits NF-kappaB, suppresses IkappaBalpha ubiquitination and modulates innate immune responses. (2008) J Immunol. 180(7):5045-56.
- Mukherjee S, Negi VS, Keitany G, Tanaka Y, Orth, K. In vitro activation of the IkappaB kinase complex by human T-cell leukemia virus type-1 Tax. (2008) J Biol Chem. 283(22):15127-33.
- Hao YH, Wang Y, Burdette D, Mukherjee S, Keitany G, Goldsmith E, Orth, K. Structura requirements for Yersinia YopJ inhibition of MAP kinase pathways. (2008) PLoS One. 3(1):e1375.
- Trosky JE, Liverman AD, Orth, K. Yersinia outer proteins: Yops. (2008) Cell Microbiol. 10(3):557-65.