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  • Review Article
  • Published:

The cytoskeleton in cell-autonomous immunity: structural determinants of host defence

Nature Reviews Immunology volume 15, pages 559–573 (2015)Cite this article

Subjects

Key Points

  • Actin, microtubules, intermediate filaments and septins are four major components of the cytoskeleton. They all have crucial roles in cell-autonomous immunity.

  • There is currently intense investigation of how cytoskeletal dynamics are regulated, and how cytoskeletal components interact and work in conjunction with cell-autonomous immunity.

  • Sensing of pathogenic bacteria is a first step in orchestrating their elimination by the immune system. During infection, bacterial effector proteins and toxins have effects on the host cytoskeleton, and new studies have identified innate immune sensors that guard against pathogen-induced manipulation of cytoskeleton proteins.

  • Crucial functions of the cytoskeleton in cell-autonomous immunity include their scaffolding role for protein recruitment at the plasma membrane and in the cytosol, and their role in subcellular compartmentalization.

  • Innate immune proteins also regulate cytoskeletal dynamics to effectively restrict bacterial pathogens, highlighting the interdependence between the cytoskeleton and cell-autonomous immunity.

  • Further investigations into the multiple roles of the cytoskeleton in host defence will help to decipher the molecular mechanisms underlying human diseases, such as cancer, neurological disorders and autoinflammatory conditions, as well as susceptibility to infections.

Abstract

Host cells use antimicrobial proteins, pathogen-restrictive compartmentalization and cell death in their defence against intracellular pathogens. Recent work has revealed that four components of the cytoskeleton — actin, microtubules, intermediate filaments and septins, which are well known for their roles in cell division, shape and movement — have important functions in innate immunity and cellular self-defence. Investigations using cellular and animal models have shown that these cytoskeletal proteins are crucial for sensing bacteria and for mobilizing effector mechanisms to eliminate them. In this Review, we highlight the emerging roles of the cytoskeleton as a structural determinant of cell-autonomous host defence.

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Figure 1: Roles for the cytoskeleton in innate immunity and cell-autonomous restriction of bacterial infection.
Figure 2: Detection of bacteria-induced cytoskeletal changes by NOD-like receptors and pyrin.
Figure 3: The roles of the cytoskeleton in innate immune signalling.
Figure 4: Cytoskeletal dynamics and cell-autonomous control of bacterial infection.

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Acknowledgements

The authors apologize that, owing to space limitations, many primary research articles of importance to the field could not be acknowledged in this Review. They thank A. Willis for preparation of some of the original figures. Work in the laboratory of S.M. is supported by a Wellcome Trust Research Career Development Fellowship (WT097411MA) and the Lister Institute of Preventive Medicine. A.R.S. would like to acknowledge funds from the Wellcome Trust (WT108246AIA), Imperial College and the Royal Society (RG130811).

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  1. Medical Research Council Centre of Molecular Bacteriology and Infection (CMBI), Imperial College London, Armstrong Road, SW7 2AZ, London, UK

    Serge Mostowy & Avinash R. Shenoy

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  1. Serge Mostowy
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Correspondence to Serge Mostowy or Avinash R. Shenoy.

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Supplementary information S1 (table)

Bacterial mechanisms to avoid or exploit autophagy (PDF 293 kb)

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Glossary

Pyrin

An inflammasome-activating protein that is not part of the nucleotide-binding and oligomerization domain (NOD)- and leucine-rich repeat (LRR)-containing protein (NLR) family. It has a PAAD (pyrin, AIM, ASC death-domain-like) domain, a DAPIN (domain in apoptosis and interferon response) domain, a PYD (pyrin amino-terminal homology domain), a tripartite motif (TRIM; containing the RING domain, B-box and coiled coil domains), and a carboxy-terminal B30.2 domain.

Inflammasomes

Large oligomeric multiprotein complexes that act as signalling platforms to catalytically activate pro-caspase 1 into its active p20 and p10 subunits, promote the maturation of interleukin-1β (IL-1β) and IL-18, and triggers pyroptosis.

Non-canonical inflammasome activation

NOD-, LRR- and pyrin domain-containing 3 (NLRP3)- and ASC-dependent activation of caspase 1 by caspase 4-mediated detection of lipo-polysaccharide that promotes caspase 1-dependent maturation of interleukin-1β (IL-1β) and IL-18, and triggers caspase 4-dependent pyroptosis.

Pyroptosis

A form of necrotic cell death that is activated by caspase 1, caspase 4 or caspase 5 and results in inflammation; morphological features include cell swelling and the formation of membrane pores, eventually leading to cell lysis.

Autophagy

A catabolic, membrane-trafficking process that involves degradation of cellular components through the actions of lysosomes.

Autolysosome

The compartment resulting from the fusion of an autophagosome with a lysosome.

Actin

A globular protein (G-actin) that forms microfilaments (F-actin) by polymerizing in an ATP-dependent manner.

Microtubules

Highly dynamic cylindrical filaments made from α- and β-tubulin heterodimers. They are formed by polymerization of tubulin in a GTP-dependent manner.

Intermediate filaments

A heterogeneous protein family that contains both nuclear and cytoplasmic proteins, which assemble into filaments intermediate in size between smaller microfilaments and larger microtubules.

Septins

Conserved family of GTP-binding proteins that assemble to form hetero-oligomeric complexes, filaments and rings.

RHO family GTPases

Small (~21 kDa) GTP-hydrolysing enzymes that cycle between their active (GTP-bound) and inactive (GDP-bound) forms and act as molecular switches.

Type III secretion system

(T3SS). A needle-like structure, also called the injectisome, used by Gram-negative bacteria to secrete proteins from the bacterial cell into the eukaryotic cell.

Guanine nucleotide exchange factor

(GEF). Factor that activates monomeric GTPases by stimulating the release of GDP to allow binding of GTP; some GEFs can activate multiple GTPases, whereas others are specific to a single GTPase.

Druggable human genes

A collection of human genes — typically from large gene families such as heterotrimeric G protein-coupled receptors, protein kinases, ion channels and ubiquitin ligases — predicted to bind small molecules that could alter their function in a therapeutically beneficial way.

Cytochalasin D

A fungal metabolite that binds to actin filaments and is used to block the polymerization and elongation of actin.

Resistance genes

(R-genes). Genes in plants that encode proteins with nucleotide-binding oligomerization domain (NOD) and leucine-rich repeat (LRR) domains, and amino-terminal interaction motifs such as Toll–IL-1 receptor (TIR) motif or coiled-coil domains.

Switch I regions

Flexible loops present in RHO GTPases that contain residues that coordinate Mg2+ and allow binding to GTP or GDP.

Necrosis

A form of lytic cell death that frequently results from toxic injury, hypoxia or stress, which is in contrast to genetically controlled programmed cell death pathways such as apoptosis. This form of cell death is usually pro-inflammatory.

CARD9-, BCL-10- and MALT1-containing complex

(CBM complex). A complex containing caspase activation and recruitment domain 9 (CARD9), B cell lymphoma 10 (BCL-10) and MALT lymphoma-associated translocation protein 1 (MALT1) that triggers nuclear factor-κB signalling downstream of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in myeloid cells.

Frustrated phagocytosis

The phenomenon of incomplete or stalled phagocytosis: that is, when a phagocyte is unable to completely engulf and internalize a target particle.

Filopodia

Actin-rich, slender projections at the leading edge of motile cells with roles in sensing, migration and cell–cell interactions.

Lamellipodia

Actin-rich projections at the leading edge of motile cells that coexist with filopodia and are essential for cellular movement along a substratum.

Diffusion barrier

A mechanism to compartmentalize cellular membranes into separate domains; diffusion barriers can be found in continuous membranes, such as the plasma and endoplasmic reticulum membranes, and restrict the diffusion of membrane-associated proteins.

Rapamycin

A pharmacological inhibitor of mammalian target of rapamycin (mTOR), which is a central regulator of cell metabolism, growth, proliferation and survival. It is used to induce autophagy or when used at high doses, it can suppress the immune system.

Leading edge

Region of intense F-actin accumulation at the front end of a migrating cell.

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Mostowy, S., Shenoy, A. The cytoskeleton in cell-autonomous immunity: structural determinants of host defence. Nat Rev Immunol 15, 559–573 (2015). https://doi.org/10.1038/nri3877

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