Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity

Youngjin Lee; Byoung Sik Kim; Sanghyeon Choi; Eun Young Lee; Shinhye Park; Jungwon Hwang; Yumi Kwon; Jaekyung Hyun; Cheolju Lee; Jihyun F. Kim; Soo Hyun Eom; Myung Hee Kima

doi:10.1073/pnas.1905095116

Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity

Youngjin Lee, Byoung Sik Kim, Sanghyeon Choi, Eun Young Lee, Shinhye Park, Jungwon Hwang, Yumi Kwon, Jaekyung Hyun, Cheolju Lee, Jihyun F. Kim, Soo Hyun Eom, Myung Hee Kima

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

Upon invading target cells, multifunctional autoprocessing repeatsin- toxin (MARTX) toxins secreted by bacterial pathogens release their disease-related modularly structured effector domains. However, it is unclear how a diverse repertoire of effector domains within these toxins are processed and activated. Here, we report that Makes caterpillars floppy-like effector (MCF)-containing MARTX toxins require ubiquitous ADP-ribosylation factor (ARF) proteins for processing and activation of intermediate effector modules, which localize in different subcellular compartments following limited processing of holo effector modules by the internal cysteine protease. Effector domains structured tandemly with MCF in intermediate modules become disengaged and fully activated by MCF, which aggressively interacts with ARF proteins present at the same location as intermediate modules and is converted allosterically into a catalytically competent protease. MCF-mediated effector processing leads ultimately to severe virulence in mice via an MCF-mediated ARF switching mechanism across subcellular compartments. This work provides insight into how bacteria take advantage of host systems to induce systemic pathogenicity.

Original language	English
Pages (from-to)	18031-18040
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	36
DOIs	https://doi.org/10.1073/pnas.1905095116
Publication status	Published - 2019 Sept 3

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank beamline staff at the Pohang Accelerator Laboratory (BL-5C and 7A), Korea, and the Photon Factory (BL-17A), Japan, for assistance during X-ray diffraction experiments. We thank all members of the M.H.K. laboratory for valuable discussion and technical support. This work was supported by the National Research Foundation of Korea, funded by the Ministry of Science and ICT of Korea (2014R1A2A1A01005971 and 2017R1A2B3007317 to M.H.K. and 2018R1C1B5045632 to B.S.K.), the Korea Research Institute of Bioscience and Biotechnology Initiative Program, and a grant from Korea Health Industry Development Institute (HI14C3484 to C.L.).

Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.

All Science Journal Classification (ASJC) codes

General

Access to Document

10.1073/pnas.1905095116

Cite this

Lee, Y., Kim, B. S., Choi, S., Lee, E. Y., Park, S., Hwang, J., Kwon, Y., Hyun, J., Lee, C., Kim, J. F., Eom, S. H., & Kima, M. H. (2019). Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity. Proceedings of the National Academy of Sciences of the United States of America, 116(36), 18031-18040. https://doi.org/10.1073/pnas.1905095116

@article{df5b857c439249f0ace6a4029fab917f,

title = "Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity",

abstract = "Upon invading target cells, multifunctional autoprocessing repeatsin- toxin (MARTX) toxins secreted by bacterial pathogens release their disease-related modularly structured effector domains. However, it is unclear how a diverse repertoire of effector domains within these toxins are processed and activated. Here, we report that Makes caterpillars floppy-like effector (MCF)-containing MARTX toxins require ubiquitous ADP-ribosylation factor (ARF) proteins for processing and activation of intermediate effector modules, which localize in different subcellular compartments following limited processing of holo effector modules by the internal cysteine protease. Effector domains structured tandemly with MCF in intermediate modules become disengaged and fully activated by MCF, which aggressively interacts with ARF proteins present at the same location as intermediate modules and is converted allosterically into a catalytically competent protease. MCF-mediated effector processing leads ultimately to severe virulence in mice via an MCF-mediated ARF switching mechanism across subcellular compartments. This work provides insight into how bacteria take advantage of host systems to induce systemic pathogenicity.",

author = "Youngjin Lee and Kim, {Byoung Sik} and Sanghyeon Choi and Lee, {Eun Young} and Shinhye Park and Jungwon Hwang and Yumi Kwon and Jaekyung Hyun and Cheolju Lee and Kim, {Jihyun F.} and Eom, {Soo Hyun} and Kima, {Myung Hee}",

note = "Funding Information: ACKNOWLEDGMENTS. We thank beamline staff at the Pohang Accelerator Laboratory (BL-5C and 7A), Korea, and the Photon Factory (BL-17A), Japan, for assistance during X-ray diffraction experiments. We thank all members of the M.H.K. laboratory for valuable discussion and technical support. This work was supported by the National Research Foundation of Korea, funded by the Ministry of Science and ICT of Korea (2014R1A2A1A01005971 and 2017R1A2B3007317 to M.H.K. and 2018R1C1B5045632 to B.S.K.), the Korea Research Institute of Bioscience and Biotechnology Initiative Program, and a grant from Korea Health Industry Development Institute (HI14C3484 to C.L.). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",

year = "2019",

month = sep,

day = "3",

doi = "10.1073/pnas.1905095116",

language = "English",

volume = "116",

pages = "18031--18040",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "36",

}

Lee, Y, Kim, BS, Choi, S, Lee, EY, Park, S, Hwang, J, Kwon, Y, Hyun, J, Lee, C, Kim, JF, Eom, SH & Kima, MH 2019, 'Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 36, pp. 18031-18040. https://doi.org/10.1073/pnas.1905095116

Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity. / Lee, Youngjin; Kim, Byoung Sik; Choi, Sanghyeon et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 36, 03.09.2019, p. 18031-18040.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity

AU - Lee, Youngjin

AU - Kim, Byoung Sik

AU - Choi, Sanghyeon

AU - Lee, Eun Young

AU - Park, Shinhye

AU - Hwang, Jungwon

AU - Kwon, Yumi

AU - Hyun, Jaekyung

AU - Lee, Cheolju

AU - Kim, Jihyun F.

AU - Eom, Soo Hyun

AU - Kima, Myung Hee

N1 - Funding Information: ACKNOWLEDGMENTS. We thank beamline staff at the Pohang Accelerator Laboratory (BL-5C and 7A), Korea, and the Photon Factory (BL-17A), Japan, for assistance during X-ray diffraction experiments. We thank all members of the M.H.K. laboratory for valuable discussion and technical support. This work was supported by the National Research Foundation of Korea, funded by the Ministry of Science and ICT of Korea (2014R1A2A1A01005971 and 2017R1A2B3007317 to M.H.K. and 2018R1C1B5045632 to B.S.K.), the Korea Research Institute of Bioscience and Biotechnology Initiative Program, and a grant from Korea Health Industry Development Institute (HI14C3484 to C.L.). Publisher Copyright: © 2019 National Academy of Sciences. All rights reserved.

PY - 2019/9/3

Y1 - 2019/9/3

N2 - Upon invading target cells, multifunctional autoprocessing repeatsin- toxin (MARTX) toxins secreted by bacterial pathogens release their disease-related modularly structured effector domains. However, it is unclear how a diverse repertoire of effector domains within these toxins are processed and activated. Here, we report that Makes caterpillars floppy-like effector (MCF)-containing MARTX toxins require ubiquitous ADP-ribosylation factor (ARF) proteins for processing and activation of intermediate effector modules, which localize in different subcellular compartments following limited processing of holo effector modules by the internal cysteine protease. Effector domains structured tandemly with MCF in intermediate modules become disengaged and fully activated by MCF, which aggressively interacts with ARF proteins present at the same location as intermediate modules and is converted allosterically into a catalytically competent protease. MCF-mediated effector processing leads ultimately to severe virulence in mice via an MCF-mediated ARF switching mechanism across subcellular compartments. This work provides insight into how bacteria take advantage of host systems to induce systemic pathogenicity.

AB - Upon invading target cells, multifunctional autoprocessing repeatsin- toxin (MARTX) toxins secreted by bacterial pathogens release their disease-related modularly structured effector domains. However, it is unclear how a diverse repertoire of effector domains within these toxins are processed and activated. Here, we report that Makes caterpillars floppy-like effector (MCF)-containing MARTX toxins require ubiquitous ADP-ribosylation factor (ARF) proteins for processing and activation of intermediate effector modules, which localize in different subcellular compartments following limited processing of holo effector modules by the internal cysteine protease. Effector domains structured tandemly with MCF in intermediate modules become disengaged and fully activated by MCF, which aggressively interacts with ARF proteins present at the same location as intermediate modules and is converted allosterically into a catalytically competent protease. MCF-mediated effector processing leads ultimately to severe virulence in mice via an MCF-mediated ARF switching mechanism across subcellular compartments. This work provides insight into how bacteria take advantage of host systems to induce systemic pathogenicity.

UR - http://www.scopus.com/inward/record.url?scp=85071788603&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071788603&partnerID=8YFLogxK

U2 - 10.1073/pnas.1905095116

DO - 10.1073/pnas.1905095116

M3 - Article

C2 - 31427506

AN - SCOPUS:85071788603

SN - 0027-8424

VL - 116

SP - 18031

EP - 18040

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 36

ER -

Makes caterpillars floppy-like effector-containing MARTX toxins require host ADP-ribosylation factor (ARF) proteins for systemic pathogenicity

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this