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Review
. 2015 Sep 15;15(9):559-73.
doi: 10.1038/nri3877. Epub 2015 Aug 21.

The Cytoskeleton in Cell-Autonomous Immunity: Structural Determinants of Host Defence

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Free PMC article
Review

The Cytoskeleton in Cell-Autonomous Immunity: Structural Determinants of Host Defence

Serge Mostowy et al. Nat Rev Immunol. .
Free PMC article

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.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Roles for the cytoskeleton in innate immunity and cell-autonomous restriction of bacterial infection. Actin, microtubules, intermediate filaments and septins have key roles in the detection of bacterial pathogens and the mobilization of antibacterial responses. a | Actin assemblies at the plasma membrane provide rigidity to the cell, act as a scaffold to restrain membrane-bound proteins (for example, receptors) and enable endocytosis of receptors, such as Toll-like receptors (TLRs) ,,–, . b | Cytoplasmic bacteria that polymerize actin, including Shigella flexneri and Mycobacterium marinum, can be trapped in septin cages, which have been shown to restrict actin-based motility and bacterial dissemination , . c | Microtubules and microtubule motors traffic cargo, such as autophagsosomes, inside the cell , . There are different types of microtubule motors: plus (+) end motors and minus (–) end motors are classified depending on the direction in which they travel along microtubules , . Autophagosomes move from peripheral locations in the cell to the microtubule organizing centre (MTOC), a major site of microtubule nucleation, where lysosomes are concentrated for autophagosome–lysosome fusion ,, . d | Extracellular F-actin on necrotic cells can act as a danger signal , . Necrosis leads to the loss of membrane integrity, exposing the actin cytoskeleton, and the exposed F-actin acts as a ligand for the C-type lectin domain family 9 member A (CLEC9A) , . e | Cytoskeleton rearrangements caused by bacterial invasion or toxins are recognized by sensors, such as the cytosolic receptors nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and pyrin, which leads to the activation of innate immune signalling pathways ,–, . f | The cytoskeleton can function as a scaffold for autophagy inhibition , ; intermediate filaments suppress autophagy by forming a complex with proteins that are crucial for autophagy initiation (for example, beclin 1) .
Figure 2
Figure 2
Detection of bacteria-induced cytoskeletal changes by NOD-like receptors and pyrin. a | Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) detects invasion by Salmonella enterica subsp. enterica serovar Typhimurium and SopE-induced actin polymerization and membrane ruffling . SopE activates the GTPases RAC1 and cell division cycle (CDC42) via its guanine nucleotide exchange factor (GEF) activity . NOD1 forms multiprotein complexes with SopE, HSP90, and active RAC1 or CDC42 (indicated by an asterisk) . After detection of peptidoglycan (PG) fragments containing d-glutamyl-meso-diaminopimelic acid (iE-DAP) ligands, activated RAC1 is essential for NOD1 signalling . Downstream signalling uses receptor-interacting protein 2 (RIP2)-dependent activation of the transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1). Constitutively active forms of RHOA (not depicted), RAC1 and CDC42 can also be sensed by NOD1 to activate RIP2-dependent transcriptional changes . b | NOD1 detects Shigella flexneri invasion. S. flexneri iE-DAP and the effector proteins IpgB2 and OspB are detected by NOD1, and this depends on actin dynamics controlled by its interacting partners GEF-H1 (which is a RHOA GEF) and Slingshot homologue 1 (SSH1; a cofilin phosphatase) , . GEF-H1 activates RHOA-dependent actin dynamics and downstream effectors such as RHO-associated protein kinase 1 (ROCK1) . SSH1 dephosphorylates cofilin, which increases its actin depolymerization activity . Downstream NF-κB activation by iE-DAP involves RHOA and RIP2, whereas NF-κB activation by OspB and IpGB2 requires RHOA and ROCK1. c | Alterations of RHOA, RHOB or RHOC by bacterial toxins (indicated by asterisks) are detected by pyrin . A number of bacterial toxins with different biochemical activities covalently modify and inhibit the indicated RHO GTPases (for more details see TABLE 1). Toxin-induced inhibition of RHO GTPases results in altered balance between F-actin and G-actin and cytoskeleton dysfunction, which is sensed by pyrin. The assembly of inflammasomes by pyrin activates caspase 1, which processes interleukin-1β (IL-1β) and IL-18, and triggers cell death by pyroptosis. ASC is an adaptor that allows the recruitment and activation of caspase 1 by pyrin. d | Actin, microtubules and vimentin intermediate filaments in NOD-, LRR- and pyrin domain-containing 3 (NLRP3) activation. Actin is required for phagocytosis of particulate agonists, such as monosodium uric acid (MSU) crystals and calcium pyrophosphate dehydrate (CPPD), to activate NLRP3 (REF. 58). The MEC17 acetylase and the sirtuin 2 (SIRT2) deacetylase modulate the levels of acetylated α-tubulin in cells . Acetylation of α-tubulin favours trafficking of mitochondria containing the adaptor protein ASC to endoplasmic reticulum (ER) sites containing NLRP3 and promotes inflammasome assembly . Vimentin intermediate filaments interact with NLRP3 and promote its activation by soluble agonists (for example, ATP–P2X7 receptor signalling) as well as particulate agonists (such as MSU crystals and asbestos) .
Figure 3
Figure 3
The roles of the cytoskeleton in innate immune signalling. a | F-actin functions as a danger signal. Surface-exposed actin on necrotic cells is detected by antigen-presenting CD8α + dendritic cells (DCs) – . Specific DC subsets express C-type lectin domain family 9 member A (CLEC9A), which is a receptor for actin. Signalling via spleen tyrosine kinase (SYK) promotes antigen cross-presentation and does not activate transcriptional responses. b | Dectin 1 signalling and phagocytosis. Signalling by dectin 1 — for example, during the detection of β-glucan particles — activates SYK-dependent and CARD9-, BCL-10- and MALT1-containing complex (CBM complex)-dependent pro-inflammatory gene expression . Inhibition of actin dynamics by cytochalasin D results in frustrated phagocytosis and heightened pro-inflammatory signalling (indicated by thicker arrows). c | The role of the cytoskeleton in endocytosis of Toll-like receptor 4 (TLR4) and maturation of TLR9-containing endosomes. TLR4 endocytosis determines signalling via myeloid differentiation primary response protein 88 (MYD88) on the plasma membrane and via TIR domain-containing adaptor protein inducing IFNβ (TRIF) on endosomes. The two adaptor proteins MYD88 and TRIF induce different transcriptional programmes, as depicted . Actin dynamics control the maturation of TLR9-containing endosomes into signalling- competent lysosome-like vesicles . Dedicator of cytokinesis 2 (DOCK2) and the GTPase RAC1 are involved in modulating actin to promote receptor trafficking and TLR9-dependent induction of type I interferons (IFNs) , . AP-1, activator protein 1; IKK, IκB kinase; IRAK, interleukin-1 receptor-associated kinase; IRF, IFN-regulatory factor; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; TAK1, TGFβ-activated kinase 1; TBK1, TANK-binding kinase 1; TNF, tumour necrosis factor; TRAF6, TNF receptor-associated factor 6.
Figure 4
Figure 4
Cytoskeletal dynamics and cell-autonomous control of bacterial infection. a | The Listeria monocytogenes protein ActA — which recruits the actin-related protein 2/3 (ARP2/3) complex and polymerizes actin tails — coats the bacterium and prevents recognition by ubiquitin, p62, nuclear dot protein (NDP52) and microtubule-associated protein 1 light chain 3 (LC3) , . Thus, L. monocytogenes avoids autophagy and septin caging by expressing ActA , (see Supplementary information S1 (table)). Alternatively, Shigella flexneri uses IcsA to recruit neuronal Wiskott–Aldrich syndrome protein (N-WASP) and ARP2/3, and polymerize actin tails . IcsA-mediated actin polymerization and recognition by autophagy critical components (ubiquitin, p62, NDP52, ATG5 and LC3) are essential both for septin cage assembly and for targeting to autophagy – . To prevent recognition of IcsA by the host cell, S. flexneri can express IcsB – (see Supplementary information S1 (table)). b | Roles of caspase 4 in actin dynamics. Caspase 4 interacts with the actin-depolymerizing WDR1–cofilin complex through its amino-terminal caspase activation and recruitment domain (CARD), and with flightless 1 via its carboxy-terminal catalytic p30 domain , . Caspase 4 controls actin depolymerization and cellular migration and is present at the leading edge in macrophages , . Restriction of intracellular growth of Legionella pneumophila requires its delivery to lysosomes, which is an actin-dependent process controlled by caspase 4 (REF. 122). c | Actin dynamics controlled by the NOD-, LRR- and CARD-containing 4 (NLRC4) inflammasome. During Salmonella enterica subsp. enterica serovar Typhimurium infection, NLRC4 is required for actin dynamics around S. Typhimurium, the assembly of inflammasome foci containing the adaptor protein ASC and the generation of mitochondrial reactive oxygen species (ROS) to restrict bacterial growth . NLRC4 signalling also leads to caspase 1 activation, maturation of interleukin-1β (IL-1β) and IL-18, and pyroptosis.

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