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CARD–BCL-10–MALT1 signalling in protective and pathological immunity

Nature Reviews Immunology volume 19, pages 118–134 (2019)Cite this article

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Abstract

CARD protein–BCL-10–MALT1 (CBM) signalosomes are multiprotein signalling platforms that control immune and inflammatory pathways in most tissues. After exposure to distinct immune triggers, these molecules form self-organizing filaments with MALT1 protease activity to regulate canonical nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways and the degradation of mRNA-binding proteins, which provides two layers of control of inflammatory gene expression. These CBM-regulated mechanisms are essential for host defence and tissue homeostasis, and numerous genetic alterations in CBM signalling components have been implicated in inherited and acquired immune-mediated diseases. This Review discusses the regulation and signalling of CBM complexes, their physiological roles and their pathophysiological functions in human immunodeficiency diseases, inflammatory disorders and cancers of the immune system.

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Fig. 1: Structural organization of CBM complex components, showing sites of post-translational modification.
Fig. 2: Cell type-specific activation of CBM complexes.
Fig. 3: Molecular mechanisms activating CBM signalling in T cells.
Fig. 4: MALT1 paracaspase substrates and their molecular functions.
Fig. 5: Cell type-specific physiological functions of CBM complex signalling.
Fig. 6: Somatic and germline alterations and coding risk variants in CARD9, CARD10, CARD11, CARD14 and MALT1.

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Acknowledgements

The authors are affiliated with the Center for Translational Cancer Research (TranslaTUM), Munich, Germany, the German Cancer Consortium (DKTK), Heidelberg, Germany, and the German Center for Infection Research (DZIF), partner site Munich, Germany. Work in the authors’ laboratory is supported by research grants from the Deutsche Forschungsgemeinschaft (SFB 1054/B01, SFB 1335/P01 and P08) and the European Research Council (FP7, grant agreement No. 322865) to J.R. and the international doctoral programme ‘i-Target: Immunotargeting of Cancer’, funded by the Elite Network of Bavaria. The authors apologize to individuals whose work could not be cited in this article owing to space constraints.

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    Jürgen Ruland & Lara Hartjes

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Glossary

Psoriasis

A chronic inflammatory skin disease that can also manifest in the joints and vasculature.

Experimental autoimmune encephalomyelitis

An animal model of the autoimmune disease multiple sclerosis, which affects the central nervous system.

Neutrophilic myeloid-derived suppressor cells

(N-MDSCs). Innate immune cells that can suppress T cell proliferation in inflammatory environments.

Crohn’s disease

An inflammatory bowel disease with abnormal immune responses and an altered commensal microbiome caused by hereditary and environmental factors.

Aryl hydrocarbon receptor

A basic helix–loop–helix transcription factor that functions as a receptor for environmental cues such as xenobiotics or metabolites.

Sezary syndrome

A leukaemic form of cutaneous T cell lymphoma.

Dermatophytes

A group of fungi causing common superficial skin and nail infections.

Ankylosing spondylitis

A form of severe arthritis primarily affecting the spine, which is caused by genetic and environmental factors.

Primary sclerosing cholangitis

A multifactorial progressive inflammatory disorder of the liver resulting in scarring of bile ducts, cholestasis and liver cirrhosis.

IgA nephropathy

A kidney disease of unknown aetiology with genetic contribution that is characterized by IgA deposits that cause glomerulonephritis and ultimately renal failure.

Primary open-angle glaucoma

A multifactorial neurodegenerative disease that primarily affects the optic nerve and is a prevalent cause of irreversible blindness.

Pityriasis rubra pilaris

(PRP). A rare chronic inflammatory skin disease related to psoriasis with distinct clinical and histopathological features.

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Ruland, J., Hartjes, L. CARD–BCL-10–MALT1 signalling in protective and pathological immunity. Nat Rev Immunol 19, 118–134 (2019). https://doi.org/10.1038/s41577-018-0087-2

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