Bcl-x L mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

X. Zhao, N. Khan, H. Gan, F. Tzelepis, Tomoyasu Nishimura, S. Y. Park, M. Divangahi, H. G. Remold

Research output: Contribution to journalArticle

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Abstract

Virulent Mycobacterium tuberculosis (Mtb) triggers necrosis in host M •, which is essential for successful pathogenesis in tuberculosis. Here we demonstrate that necrosis of Mtb-infected M • is dependent on the action of the cytosolic Receptor Interacting Protein Kinase 3 (RIPK3) and the mitochondrial Bcl-2 family member protein B-cell lymphoma - extra large (Bcl-x L). RIPK3-deficient M • are able to better control bacterial growth in vitro and in vivo. Mechanistically, cytosolic RIPK3 translocates to the mitochondria where it promotes necrosis and blocks caspase 8-activation and apoptosis via Bcl-x L. Furthermore, necrosis is associated with stabilization of hexokinase II on the mitochondria as well as cyclophilin D-dependent mitochondrial permeability transition. Collectively, these events upregulate the level of reactive oxygen species to induce necrosis. Thus, in Mtb-infected M •, mitochondria are an essential platform for induction of necrosis by activating RIPK3 function and preventing caspase 8-activation.

Original languageEnglish
Pages (from-to)1553-1568
Number of pages16
JournalMucosal Immunology
Volume10
Issue number6
DOIs
Publication statusPublished - 2017 Nov 1

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Receptor-Interacting Protein Serine-Threonine Kinases
B-Cell Lymphoma
Protein Kinases
Tuberculosis
Necrosis
Macrophages
Mycobacterium tuberculosis
Mitochondria
Caspase 8
Hexokinase
Permeability
Reactive Oxygen Species
Up-Regulation
Apoptosis
Growth

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Zhao, X., Khan, N., Gan, H., Tzelepis, F., Nishimura, T., Park, S. Y., ... Remold, H. G. (2017). Bcl-x L mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages. Mucosal Immunology, 10(6), 1553-1568. https://doi.org/10.1038/mi.2017.12

Bcl-x L mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages. / Zhao, X.; Khan, N.; Gan, H.; Tzelepis, F.; Nishimura, Tomoyasu; Park, S. Y.; Divangahi, M.; Remold, H. G.

In: Mucosal Immunology, Vol. 10, No. 6, 01.11.2017, p. 1553-1568.

Research output: Contribution to journalArticle

Zhao, X, Khan, N, Gan, H, Tzelepis, F, Nishimura, T, Park, SY, Divangahi, M & Remold, HG 2017, 'Bcl-x L mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages', Mucosal Immunology, vol. 10, no. 6, pp. 1553-1568. https://doi.org/10.1038/mi.2017.12
Zhao, X. ; Khan, N. ; Gan, H. ; Tzelepis, F. ; Nishimura, Tomoyasu ; Park, S. Y. ; Divangahi, M. ; Remold, H. G. / Bcl-x L mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages. In: Mucosal Immunology. 2017 ; Vol. 10, No. 6. pp. 1553-1568.
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