Immobile ligands enhance FcγR-TLR2/1 crosstalk by promoting interface overlap of receptor clusters

Li, Miao; Lee, Seonik; Zahedian, Maryam; Ding, Chuan‐Fan; Yan, Jun; Yu, Yan

doi:10.1016/j.bpj.2022.02.010

Cited by 4 publications

(4 citation statements)

References 49 publications

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“…For instance, studies suggested that TLR2 and Dectin-1 signals converge on caspase recruitment domain family member 9 (CARD9) to activate the transcription factor NF-κB. − When receptor clusters interact at the interfaces, different types of receptors may be able to intermix or separate more rapidly to regulate their crosstalk compared to the colocalization models in which different species of receptors completely intermix. Interestingly, we have also found recently that TLR2 and Fc gamma receptor (FcγR) form discrete receptor nanoclusters that become partially overlapped during synergistic signaling . Future studies are needed to explore whether this model of receptor clusters intermixing at interfaces is a common mechanism shared by many immune receptors that have signaling crosstalk.…”

Section: Discussionmentioning

confidence: 96%

“…Interestingly, we have also found recently that TLR2 and Fc gamma receptor (FcγR) form discrete receptor nanoclusters that become partially overlapped during synergistic signaling. 53 Future studies are needed to explore whether this model of receptor clusters intermixing at interfaces is a common mechanism shared by many immune receptors that have signaling crosstalk. Further, the expression level of receptors, such as Dectin-1, 13 varies among different types of cells in physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

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Spatial Organization of Dectin-1 and TLR2 during Synergistic Crosstalk Revealed by Super-resolution Imaging

Vultorius

Bethi

et al. 2022

J. Phys. Chem. B

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Innate immune cells recognize and elicit responses against pathogens by integrating signals from different types of cellsurface receptors. How the receptors interact in the membrane to enable their signaling crosstalk is poorly understood. Here, we reveal the nanoscale organization of TLR2 and Dectin-1, a receptor pair known to cooperate in regulating antifungal immunity, through their synergistic signaling crosstalk at macrophage cell membranes. Using super-resolution single-molecule localization microscopy, we show that discrete noncolocalized nanoclusters of Dectin-1 and TLR2 are partially overlapped during their synergistic crosstalk. Compared to when one type of receptor is activated alone, the simultaneous activation of Dectin-1 and TLR2 leads to a higher percentage of both receptors being activated by their specific ligands and consequently an increased level of tyrosine phosphorylation. Our results depict, in nanoscale detail, how Dectin-1 and TLR2 achieve synergistic signaling through the spatial organization of their receptor nanoclusters.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Spatial Organization of Dectin-1 and TLR2 during Synergistic Crosstalk Revealed by Super-resolution Imaging

Vultorius

Bethi

et al. 2022

J. Phys. Chem. B

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“…Taken together these results demonstrate that signalling proceeds through the formation of stable, long-lived, immobile nanoclusters, which disassemble when signalling is stopped. Similarly, immobilization of receptors required for signalling has also been shown for other transmembrane receptors such as EGFR [91], B-cell receptors [92, 93], T cell receptor [94], macrophage Toll-like receptor 2 [95]. In addition, it is not single molecule immobilization but a multi-molecular nanocluster immobilization that forms in response to external signalling and is required to organize downstream signalling.…”

Section: Discussionmentioning

confidence: 99%

Nano-clusters of ligand-activated integrins organize immobile, signalling active, nano-clusters of phosphorylated FAK required for mechanosignaling in focal adhesions

Jain,

Minhaj,

Kanchanawong

et al. 2024

Preprint

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Transmembrane signalling receptors, such as integrins, organise as nanoclusters that are thought to provide several advantages including, increasing avidity, sensitivity (increasing the signal-to-noise ratio) and robustness (signalling above a threshold rather than activation by a single receptor) of the signal compared to signalling by single receptors. Compared to large micron-sized clusters, nanoclusters offer the advantage of rapid turnover for the disassembly of the signal. However, if nanoclusters function as signalling hubs remains poorly understood. Here, we employ fluorescence nanoscopy combined with photoactivation and photobleaching at sub-diffraction limited resolution of ∼100nm length scale within a focal adhesion to examine the dynamics of diverse focal adhesion proteins. We show that (i) subregions of focal adhesions are enriched in immobile population of integrin β3 organised as nanoclusters, which (ii) in turn serve to organise nanoclusters of associated key adhesome proteins-vinculin, focal adhesion kinase (FAK) and paxillin, demonstrating that signalling proceeds by formation of nanoclusters rather than through individual proteins. (iii) Distinct focal adhesion protein nanoclusters exhibit distinct dynamics dependent on function. (iv) long-lived nanoclusters function as signalling hubs-wherein phosphorylated FAK and paxillin formed stable nanoclusters in close proximity to immobile integrin nanoclusters which are disassembled in response to inactivation signal by phosphatase PTPN12 (v) signalling takes place in response to an external signal such as force or geometric arrangement of the nanoclusters and when the signal is removed, these nanoclusters disassemble. Taken together, these results demonstrate that signalling downstream of transmembrane receptors is organised as hubs of signalling proteins (FAK, paxillin, vinculin) seeded by nanoclusters of the transmembrane receptor (integrin).

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“…Interestingly, we have also found recently that TLR2 and FcγR form discrete receptor nanoclusters that become partially overlapped during synergistic signaling. 51 It remains to be explored further whether this model of receptor clusters intermixing at interfaces is a common mechanism shared by many immune receptors that have signaling crosstalk.…”

Section: Discussionmentioning

confidence: 99%

Spatial organization of Dectin-1 and TLR2 during synergistic crosstalk revealed by super-resolution imaging

Vultorius

Bethi

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Innate immune cells recognize and elicit responses against pathogens by integrating signals from different types of cell-surface receptors. How the receptors interact in the membrane to enable their signaling crosstalk is poorly understood. Here, we reveal the nanoscale organization of TLR2 and Dectin-1, a receptor pair known to cooperate in regulating antifungal immunity, through their synergistic signaling crosstalk at macrophage cell membranes. Using super-resolution single-molecule localization microscopy, we show that discrete non-colocalized nanoclusters of Dectin-1 and TLR2 are partially overlapped during their synergistic crosstalk. Compared to when one type of receptor is activated alone, the simultaneous activation of Dectin-1 and TLR2 leads to a higher percentage of both receptors being activated by their specific ligands, and consequently an increased level of tyrosine phosphorylation. Our results depict, in nanoscale detail, how Dectin-1 and TLR2 achieve synergistic signaling through the spatial organization of their receptor nanoclusters.

show abstract

Immobile ligands enhance FcγR-TLR2/1 crosstalk by promoting interface overlap of receptor clusters

Cited by 4 publications

References 49 publications

Spatial Organization of Dectin-1 and TLR2 during Synergistic Crosstalk Revealed by Super-resolution Imaging

Spatial Organization of Dectin-1 and TLR2 during Synergistic Crosstalk Revealed by Super-resolution Imaging

Nano-clusters of ligand-activated integrins organize immobile, signalling active, nano-clusters of phosphorylated FAK required for mechanosignaling in focal adhesions

Spatial organization of Dectin-1 and TLR2 during synergistic crosstalk revealed by super-resolution imaging

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