Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 106 (17): 7179-7184

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MICROBIOLOGY

Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

Joachim H. C. Ortha,1, Inga Preussa,b,1, Ines Festera, Andreas Schlosserc, Brenda A. Wilsond, and Klaus Aktoriesa,2

aInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, D-79104 Freiburg, Germany; bFaculty of Biology, Albert-Ludwigs-Universität Freiburg, Schaenzlestrasse 1, 79104 Freiburg, Germany; cZentrum für Biosystemanalyse, Albert-Ludwigs-Universität Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; and dDepartment of Microbiology, University of Illinois at Urbana-Champaign, 601 South Goodwin, Urbana, IL 61801

Edited by R. John Collier, Harvard Medical School, Boston, MA, and approved March 11, 2009

Received for publication January 7, 2009.

Abstract: Pasteurella multocida toxin is a major virulence factor of Pasteurella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The {approx}145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the G{alpha}q, G{alpha}i, and G{alpha}12/13 families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of G{alpha}i2 to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of G{alpha}i and causes persistent activation of the G protein. A similar modification is also evident for G{alpha}q, but not for the closely related G{alpha}11, which is not a substrate of Pasteurella multocida toxin. Our data identify the {alpha}-subunits of heterotrimeric G proteins as the direct molecular target of Pasteurella multocida toxin and indicate that the toxin does not act like a protease, which was suggested from its thiol protease-like catalytic triad, but instead causes constitutive activation of G proteins by deamidase activity.

Key Words: bacterial protein toxin • Gi protein • posttranslational modification • transglutaminase

Author contributions: J.H.C.O. and K.A. designed research; J.H.C.O., I.P., I.F., A.S., and B.A.W. performed research; J.H.C.O., I.P., I.F., and K.A. analyzed data; and J.H.C.O., B.A.W., and K.A. wrote the paper.

1J.H.C.O. and I.P. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0900160106/DCSupplemental.

2To whom correspondence should be addressed. E-mail: klaus.aktories{at}pharmakol.uni-freiburg.de

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Substrate specificity of Pasteurella multocida toxin for {alpha} subunits of heterotrimeric G proteins.
J. H. C. Orth, I. Fester, P. Siegert, M. Weise, U. Lanner, S. Kamitani, T. Tachibana, B. A. Wilson, A. Schlosser, Y. Horiguchi, et al. (2013)
FASEB J 27, 832-842
   Abstract »    Full Text »    PDF »
Mammalian Target of Rapamycin Complex 1 (mTORC1) Plays a Role in Pasteurella multocida Toxin (PMT)-induced Protein Synthesis and Proliferation in Swiss 3T3 Cells.
H. Oubrahim, A. Wong, B. A. Wilson, and P. B. Chock (2013)
J. Biol. Chem. 288, 2805-2815
   Abstract »    Full Text »    PDF »
Structural mechanism of ubiquitin and NEDD8 deamidation catalyzed by bacterial effectors that induce macrophage-specific apoptosis.
Q. Yao, J. Cui, J. Wang, T. Li, X. Wan, T. Luo, Y.-N. Gong, Y. Xu, N. Huang, and F. Shao (2012)
PNAS 109, 20395-20400
   Abstract »    Full Text »    PDF »
Protective Immunity Conferred by the C-Terminal Fragment of Recombinant Pasteurella multocida Toxin.
J. Lee, H.-E. Kang, and H.-J. Woo (2012)
Clin. Vaccine Immunol. 19, 1526-1531
   Abstract »    Full Text »    PDF »
Bacterial effector binds host cell adenylyl cyclase to potentiate G{alpha}s-dependent cAMP production.
A. T. Pulliainen, K. Pieles, C. S. Brand, B. Hauert, A. Bohm, M. Quebatte, A. Wepf, M. Gstaiger, R. Aebersold, C. W. Dessauer, et al. (2012)
PNAS 109, 9581-9586
   Abstract »    Full Text »    PDF »
A Burkholderia pseudomallei Toxin Inhibits Helicase Activity of Translation Factor eIF4A.
A. Cruz-Migoni, G. M. Hautbergue, P. J. Artymiuk, P. J. Baker, M. Bokori-Brown, C.-T. Chang, M. J. Dickman, A. Essex-Lopresti, S. V. Harding, N. M. Mahadi, et al. (2011)
Science 334, 821-824
   Abstract »    Full Text »    PDF »
Pasteurella multocida Toxin-Stimulated Osteoclast Differentiation Is B Cell Dependent.
D. Hildebrand, K. Heeg, and K. F. Kubatzky (2011)
Infect. Immun. 79, 220-228
   Abstract »    Full Text »    PDF »
Characterization of the Membrane-targeting C1 Domain in Pasteurella multocida Toxin.
S. Kamitani, K. Kitadokoro, M. Miyazawa, H. Toshima, A. Fukui, H. Abe, M. Miyake, and Y. Horiguchi (2010)
J. Biol. Chem. 285, 25467-25475
   Abstract »    Full Text »    PDF »
Identification of a conserved membrane localization domain within numerous large bacterial protein toxins.
B. Geissler, R. Tungekar, and K. J. F. Satchell (2010)
PNAS 107, 5581-5586
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882