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

  1. Sá-Pessoa, Joana
  2. López-Montesino, Sara
  3. Przybyszewska, Kornelia
  4. Rodríguez-Escudero, Isabel 1
  5. Marshall, Helina
  6. Ova, Adelia
  7. Schroeder, Gunnar N.
  8. Barabas, Peter
  9. Molina, María
  10. Curtis, Tim
  11. Cid, Víctor J.
  12. Bengoechea, José A.
  1. 1 Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid and Instituto Ramón y Cajal de Investigaciones Sanitarias
  2. 2 Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
Revista:
Nature Communications

ISSN: 2041-1723

Año de publicación: 2023

Volumen: 14

Número: 1

Tipo: Artículo

DOI: 10.1038/S41467-023-36629-3 PMID: 36797302 SCOPUS: 2-s2.0-85148263369 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Nature Communications

Objetivos de desarrollo sostenible

Resumen

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.

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We thank the members of the J.A.B. laboratory for their thoughtful discussions and support with this project. We thank members of the V.J.C/M.M lab, especially E. del Val and J.M. Coronas-Serna for sharing MMM1 and MDM34 constructs. Research at the V.J.C and M.M. lab was funded by Grant PID2019-105342GB-I00 from Ministerio de Ciencia e Innovación (Spain) and by Grant S2017/BMD-3691-InGEMICS-CM, funded by Comunidad de Madrid and European Structural and Investment Funds. S.L-M. was recipient of predoctoral contracts by Universidad Complutense de Madrid (UCM) (Spain) and PEJD-2019-PRE/BMD-16928 by Comunidad de Madrid. This work was supported by Biotechnology and Biological Sciences Research Council (BBSRC, BB/T001976/1, BB/P020194/1, BB/N00700X/1, BB/V007939/1) to J.A.B.

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