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Organellar homeostasis and innate immune sensing

Abstract

A cell is delimited by numerous borders that define specific organelles. The walls of some organelles are particularly robust, such as in mitochondria or endoplasmic reticulum, but some are more fluid such as in phase-separated stress granules. Either way, all organelles can be damaged at times, leading their contents to leak out into the surrounding environment. Therefore, an elegant way to construct an innate immune defence system is to recognize host molecules that do not normally reside within a particular compartment. Here, we provide several examples where organellar homeostasis is lost, leading to the activation of a specific innate immune sensor; these include NLRP3 activation owing to a disrupted trans-Golgi network, Pyrin activation due to cytoskeletal damage, and cGAS–STING activation following the leakage of nuclear or mitochondrial DNA. Frequently, organelle damage is observed downstream of pathogenic infection but it can also occur in sterile settings as associated with auto-inflammatory disease. Therefore, understanding organellar homeostasis is central to efforts that will identify new innate immune pathways, and therapeutics that balance organellar homeostasis, or target the breakdown pathways that trigger innate immune sensors, could be useful treatments for infection and chronic inflammatory diseases.

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Fig. 1: Loss of nuclear homeostasis triggers innate immune sensors.
Fig. 2: Loss of mitochondrial homeostasis triggers innate immune sensors.
Fig. 3: ER stress triggers innate immune sensors.
Fig. 4: Loss of ribosome homeostasis triggers innate immune sensors.
Fig. 5: Loss of Golgi homeostasis triggers innate immune sensors.
Fig. 6: Loss of lysosomal homeostasis triggers innate immune sensors.
Fig. 7: Loss of cytoskeletal homeostasis triggers innate immune sensors.
Fig. 8: Loss of membraneless organelle homeostasis triggers innate immune sensors.

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Acknowledgements

S.L.M. acknowledges funding from NHMRC grant (2003159), The Sylvia and Charles Viertel Foundation, and HHMI-Wellcome International Research Scholarship. S.L.M. is a scientific advisor for IFM therapeutics and NRG therapeutics. A.S. is supported by the DFG (GRK2168) and the University of Melbourne through the International Research and Research Training Fund and is a student in the Bonn-Melbourne PhD program IRTG2168 (DFG).

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Correspondence to Seth L. Masters.

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S.L.M. is a scientific advisor for IFM therapeutics and NRG therapeutics. The other authors declare no competing interests.

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Nature Reviews Immunology thanks G. Nunez, H. Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Micronuclei

Small extra-nuclear structures often containing damaged chromosome fragments or whole chromosomes.

Necrosis

An unregulated form of cell death resulting from internal or external stressors.

Cathepsin

Family of lysosomal cysteine proteases.

Oxidative stress

Form of cellular stress caused by an imbalance of the production and accumulation of oxygen species.

Nucleoids

Region within prokaryotic cells that contains majority of genetic material.

Peptidoglycan

Structural element of bacterial cell walls consisting of glycan strands cross linked by peptides.

Mucin

Group of highly glycosylated proteins that are the primary constituents of mucus.

Anterograde

Pathway of transport that newly synthesized proteins take from the endoplasmic reticulum to the Golgi.

Retrograde

Pathway of transport from the Golgi to the endoplasmic reticulum.

Autophagosome

Double-layered membrane vesicle involved in intracellular degradation pathway.

Endolysosomes

Structure resulting in the fusion between lysosomes and endosomes.

Geranylation

Form of post-translational modification.

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Harapas, C.R., Idiiatullina, E., Al-Azab, M. et al. Organellar homeostasis and innate immune sensing. Nat Rev Immunol 22, 535–549 (2022). https://doi.org/10.1038/s41577-022-00682-8

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