A Non-death Function of the Mitochondrial Apoptosis Apparatus in Immunity

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2019 Apr 14

PMID 30979778

Citations 63

Authors

Dominik Brokatzky

Benedikt Dorflinger

Aladin Haimovici

Arnim Weber

Susanne Kirschnek

Juliane Vier

Arlena Metz

Julia Henschel

Tobias Steinfeldt

Ian E Gentle

Georg Hacker

Affiliations

Soon will be listed here.

Abstract

Apoptosis is a frequent form of programmed cell death, but the apoptotic signaling pathway can also be engaged at a low level, in the absence of cell death. We here report that such sub-lethal engagement of mitochondrial apoptosis signaling causes the secretion of cytokines from human epithelial cells in a process controlled by the Bcl-2 family of proteins. We further show that sub-lethal signaling of the mitochondrial apoptosis pathway is initiated by infections with all tested viral, bacterial, and protozoan pathogens and causes damage to the genomic DNA. Epithelial cells infected with these pathogens secreted cytokines, and this cytokine secretion upon microbial infection was substantially reduced if mitochondrial sub-lethal apoptosis signaling was blocked. In the absence of mitochondrial pro-apoptotic signaling, the ability of epithelial cells to restrict intracellular bacterial growth was impaired. Triggering of the mitochondrial apoptosis apparatus thus not only causes apoptosis but also has an independent role in immune defense.

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References

Roers A, Hiller B, Hornung V . Recognition of Endogenous Nucleic Acids by the Innate Immune System. Immunity. 2016; 44(4):739-54. DOI: 10.1016/j.immuni.2016.04.002. View

McArthur K, Whitehead L, Heddleston J, Li L, Padman B, Oorschot V . BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 2018; 359(6378). DOI: 10.1126/science.aao6047. View

Weber A, Heinlein M, Dengjel J, Alber C, Singh P, Hacker G . The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis. EMBO Rep. 2016; 17(5):724-38. PMC: 5341510. DOI: 10.15252/embr.201541392. View

Randow F, MacMicking J, James L . Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science. 2013; 340(6133):701-6. PMC: 3863583. DOI: 10.1126/science.1233028. View

Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S . A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998; 391(6662):43-50. DOI: 10.1038/34112. View

Dudek A, Pfaff F, Bolte H, Waguia Kontchou C, Schwemmle M . Partial Inactivation of the Chromatin Remodelers SMARCA2 and SMARCA4 in Virus-Infected Cells by Caspase-Mediated Cleavage. J Virol. 2018; 92(16). PMC: 6069203. DOI: 10.1128/JVI.00343-18. View

Dunphy G, Flannery S, Almine J, Connolly D, Paulus C, Jonsson K . Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and IFI16 Mediates NF-κB Signaling after Nuclear DNA Damage. Mol Cell. 2018; 71(5):745-760.e5. PMC: 6127031. DOI: 10.1016/j.molcel.2018.07.034. View

Ferrer P, Potthoff S, Kirschnek S, Gasteiger G, Kastenmuller W, Ludwig H . Induction of Noxa-mediated apoptosis by modified vaccinia virus Ankara depends on viral recognition by cytosolic helicases, leading to IRF-3/IFN-β-dependent induction of pro-apoptotic Noxa. PLoS Pathog. 2011; 7(6):e1002083. PMC: 3116819. DOI: 10.1371/journal.ppat.1002083. View

Corcoran J, Saffran H, Duguay B, Smiley J . Herpes simplex virus UL12.5 targets mitochondria through a mitochondrial localization sequence proximal to the N terminus. J Virol. 2009; 83(6):2601-10. PMC: 2648271. DOI: 10.1128/JVI.02087-08. View

10.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

11.

Vaux D, Haecker G, Strasser A . An evolutionary perspective on apoptosis. Cell. 1994; 76(5):777-9. DOI: 10.1016/0092-8674(94)90350-6. View

12.

Riley J, Quarato G, Cloix C, Lopez J, OPrey J, Pearson M . Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 2018; 37(17). PMC: 6120664. DOI: 10.15252/embj.201899238. View

13.

Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno A, Le Toumelin-Braizat G . The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016; 538(7626):477-482. DOI: 10.1038/nature19830. View

14.

Strasser A, Vaux D . Viewing BCL2 and cell death control from an evolutionary perspective. Cell Death Differ. 2017; 25(1):13-20. PMC: 5729521. DOI: 10.1038/cdd.2017.145. View

15.

Roos D, Donald R, Morrissette N, Moulton A . Molecular tools for genetic dissection of the protozoan parasite Toxoplasma gondii. Methods Cell Biol. 1994; 45:27-63. DOI: 10.1016/s0091-679x(08)61845-2. View

16.

Doench J, Fusi N, Sullender M, Hegde M, Vaimberg E, Donovan K . Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat Biotechnol. 2016; 34(2):184-191. PMC: 4744125. DOI: 10.1038/nbt.3437. View

17.

Agaisse H, Derre I . A C. trachomatis cloning vector and the generation of C. trachomatis strains expressing fluorescent proteins under the control of a C. trachomatis promoter. PLoS One. 2013; 8(2):e57090. PMC: 3575495. DOI: 10.1371/journal.pone.0057090. View

18.

Tyas L, Brophy V, Pope A, Rivett A, Tavare J . Rapid caspase-3 activation during apoptosis revealed using fluorescence-resonance energy transfer. EMBO Rep. 2001; 1(3):266-70. PMC: 1083724. DOI: 10.1093/embo-reports/kvd050. View

19.

Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K . Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol. 2017; 19(9):1116-1129. PMC: 5624512. DOI: 10.1038/ncb3596. View

20.

Chumduri C, Gurumurthy R, Zietlow R, Meyer T . Subversion of host genome integrity by bacterial pathogens. Nat Rev Mol Cell Biol. 2016; 17(10):659-73. DOI: 10.1038/nrm.2016.100. View