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A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection

Author

Listed:
  • Joana Sá-Pessoa

    (Queen’s University Belfast)

  • Sara López-Montesino

    (Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid and Instituto Ramón y Cajal de Investigaciones Sanitarias)

  • Kornelia Przybyszewska

    (Queen’s University Belfast)

  • Isabel Rodríguez-Escudero

    (Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid and Instituto Ramón y Cajal de Investigaciones Sanitarias)

  • Helina Marshall

    (Queen’s University Belfast)

  • Adelia Ova

    (Queen’s University Belfast)

  • Gunnar N. Schroeder

    (Queen’s University Belfast)

  • Peter Barabas

    (Queen’s University Belfast)

  • María Molina

    (Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid and Instituto Ramón y Cajal de Investigaciones Sanitarias)

  • Tim Curtis

    (Queen’s University Belfast)

  • Víctor J. Cid

    (Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid and Instituto Ramón y Cajal de Investigaciones Sanitarias)

  • José A. Bengoechea

    (Queen’s University Belfast)

Abstract

Bacteria can inhibit the growth of other bacteria by injecting effectors using a type VI secretion system (T6SS). T6SS effectors can also be injected into eukaryotic cells to facilitate bacterial survival, often by targeting the cytoskeleton. Here, we show that the trans-kingdom antimicrobial T6SS effector VgrG4 from Klebsiella pneumoniae triggers the fragmentation of the mitochondrial network. VgrG4 colocalizes with the endoplasmic reticulum (ER) protein mitofusin 2. VgrG4 induces the transfer of Ca2+ from the ER to the mitochondria, activating Drp1 (a regulator of mitochondrial fission) thus leading to mitochondrial network fragmentation. Ca2+ elevation also induces the activation of the innate immunity receptor NLRX1 to produce reactive oxygen species (ROS). NLRX1-induced ROS limits NF-κB activation by modulating the degradation of the NF-κB inhibitor IκBα. The degradation of IκBα is triggered by the ubiquitin ligase SCFβ-TrCP, which requires the modification of the cullin-1 subunit by NEDD8. VgrG4 abrogates the NEDDylation of cullin-1 by inactivation of Ubc12, the NEDD8-conjugating enzyme. Our work provides an example of T6SS manipulation of eukaryotic cells via alteration of the mitochondria.

Suggested Citation

  • Joana Sá-Pessoa & Sara López-Montesino & Kornelia Przybyszewska & Isabel Rodríguez-Escudero & Helina Marshall & Adelia Ova & Gunnar N. Schroeder & Peter Barabas & María Molina & Tim Curtis & Víctor J., 2023. "A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36629-3
    DOI: 10.1038/s41467-023-36629-3
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    References listed on IDEAS

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    1. Simone M. Haag & Muhammet F. Gulen & Luc Reymond & Antoine Gibelin & Laurence Abrami & Alexiane Decout & Michael Heymann & F. Gisou van der Goot & Gerardo Turcatti & Rayk Behrendt & Andrea Ablasser, 2018. "Targeting STING with covalent small-molecule inhibitors," Nature, Nature, vol. 559(7713), pages 269-273, July.
    2. Chris B. Moore & Daniel T. Bergstralh & Joseph A. Duncan & Yu Lei & Thomas E. Morrison & Albert G. Zimmermann & Mary A. Accavitti-Loper & Victoria J. Madden & Lijun Sun & Zhengmao Ye & John D. Lich & , 2008. "NLRX1 is a regulator of mitochondrial antiviral immunity," Nature, Nature, vol. 451(7178), pages 573-577, January.
    3. Jonathan R. Friedman & Jodi Nunnari, 2014. "Mitochondrial form and function," Nature, Nature, vol. 505(7483), pages 335-343, January.
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