MyD88 Death-Domain Oligomerization Determines Myddosome Architecture: Implications for Toll-like Receptor Signaling

Moncrieffe, Martin C.; Bollschweiler, Daniel; Li, Bing; Penczek, Pawel A.; Hopkins, Lee; Bryant, Clare E.; Klenerman, David

doi:10.1016/j.str.2020.01.003

Cited by 58 publications

(65 citation statements)

References 47 publications

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“…5F). Microscopy and biochemical analysis have suggested that oligomers of MyD88 might be present in the cytosol before TLR/IL1R activation (Moncrieffe et al, 2020) . While our data does not exclude the presence of preassembled MyD88 oligomers, we found MyD88 oligomerization was inducible and preceded IRAK4/1 recruitment ( Fig 3A and Fig.…”

Section: Myddosomes Assemble On Demand With An Ordered Molecular Chormentioning

confidence: 99%

“…Like the Myddosome, the Fas-FADD complexes have defined ratios of 5:5 (Wang et al, 2010) . However, how can this be reconciled with DD proteins, such as MyD88, and FADD forming open-ended filaments (Fu et al, 2016;Moncrieffe et al, 2020) ? In this study, we observed that loss of IRAK4 results in unchecked MyD88 oligomerization in response to IL1 stimulation ( Fig.…”

Section: Irak4 Regulates Myd88 Oligomer Size During Signal Transductionmentioning

confidence: 99%

“…MyD88 polymerization triggers the recruitment of IRAK4 followed by IRAK2 (or the functionally redundant IRAK1 (Kawagoe et al, 2008) ). However, purified MyD88 death domains and full length protein can polymerize into helical open-ended filaments in vitro (Moncrieffe et al, 2020;Motshwene et al, 2009;O'Carroll et al, 2018) . It remains unclear how the size of MyD88 oligomers is controlled in vivo .…”

Section: Introductionmentioning

confidence: 99%

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On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

Deliz-Aguirre¹,

Cao²,

Gerpott³

et al. 2020

Preprint

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A recurring feature of innate immune receptor signaling is the self-assembly of signaling proteins into oligomeric complexes. The Myddosome is an oligomeric complex that is required to transmit inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for how Myddosome proteins self-assemble and regulate intracellular signaling remains poorly understood. Here, we developed a novel assay to analyze the spatiotemporal dynamics of IL1R and Myddosome signaling in live cells. We found that MyD88 oligomerization is inducible and initially reversible. Moreover, the formation of larger, stable oligomers consisting of more than 4 MyD88s triggers the sequential recruitment of IRAK4 and IRAK1. Notably, genetic knockout of IRAK4 enhanced MyD88 oligomerization, indicating that IRAK4 controls MyD88 oligomer size and growth. MyD88 oligomer size thus functions as a physical threshold to trigger downstream signaling. These results provide a mechanistic basis for how protein oligomerization might function in cell signaling pathways.

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Section: Myddosomes Assemble On Demand With An Ordered Molecular Chormentioning

confidence: 99%

Section: Irak4 Regulates Myd88 Oligomer Size During Signal Transductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

Deliz-Aguirre¹,

Cao²,

Gerpott³

et al. 2020

Preprint

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“…With regard to negative regulation of TLR signaling, we show that the BCAP TIR domain requires indirect dimerization via its DBB domain to inhibit TLR signaling in NF-kB reporter assays. We also find that the BCAP TIR alone enhances signaling by MyD88 and MAL possibly because the monomeric BCAP TIR destabilizes autoinhibited MyD88, triggering Myddosome assembly (28). Although stable dimers of animal TIR domains have not been demonstrated, this form of indirect dimerization through an adjacent domain is seen with SARM, another negative regulator of the TLR pathways (29).…”

Section: Discussionmentioning

confidence: 72%

Negative Regulation of TLR Signaling by BCAP Requires Dimerization of Its DBB Domain

Lauenstein

Scherm

Udgata

et al. 2020

The Journal of Immunology

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The B cell adaptor protein (BCAP) is a multimodular regulator of inflammatory signaling in diverse immune system cells. BCAP couples TLR signaling to phosphoinositide metabolism and inhibits MyD88-directed signal transduction. BCAP is recruited to the TLR signalosome forming multitypic interactions with the MAL and MyD88 signaling adaptors. In this study, we show that indirect dimerization of BCAP TIR is required for negative regulation of TLR signaling. This regulation is mediated by a transcription factor Ig (TIG/IPT) domain, a fold found in the NF-kB family of transcription factors. We have solved the crystal structure of the BCAP TIG and find that it is most similar to that of early B cell factor 1 (EBF1). In both cases, the dimer is stabilized by a helixloop-helix motif at the C terminus and interactions between the b-sheets of the Ig domains. BCAP is exclusively localized in the cytosol and is unable to bind DNA. Thus, the TIG domain is a promiscuous dimerization module that has been appropriated for a range of regulatory functions in gene expression and signal transduction.

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“…We used physical properties of Carma1 and Bcl10 to inform the interaction probabilities in the simulations. Bcl10 is 33 kDa and its cytosolic diffusion constant is on the order of D Bcl10 ≈ 10 µm 2 /s, whereas Carma1 is 130 kDa and thus has a cytosolic diffusion constant on the order of D Carma1 ≈ 1 µm 2 /s (39). Via diffusion, the time it takes to traverse some distance d is t = d 2 /6D.…”

Section: Simulations Of Bcl10 Filament Growth and Degradationmentioning

confidence: 99%

Signaling through polymerization and degradation: Analysis and simulations of T cell activation mediated by Bcl10

Campanello

Traver

Shroff

et al. 2020

Preprint

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The adaptive immune system serves as a potent and highly specific defense mechanism against pathogen infection. One component of this system, the effector T cell, facilitates pathogen clearance upon detection of specific antigens by the T cell receptor (TCR). A critical process in effector T cell activation is transmission of signals from the TCR to a key transcriptional regulator, NF-κB. The transmission of this signal involves a highly dynamic process in which helical filaments of Bcl10, a key protein constituent of the TCR signaling cascade, undergo competing processes of polymeric assembly and macroautophagydependent degradation. Through computational analysis of three-dimensional super-resolution microscopy data, we quantitatively characterized TCR-stimulated Bcl10 filament assembly and length dynamics, demonstrating that filaments become shorter over time. Additionally, we developed an imagebased bootstrap-like resampling method to quantitatively demonstrate preferred association between autophagosomes and Bcl10-filament ends and punctate-Bcl10 structures, implying that autophagosomedriven macroautophagy is directly responsible for Bcl10 filament shortening. We probe Bcl10 polymerization-depolymerization dynamics with a stochastic Monte-Carlo simulation of nucleation-limited filament assembly and degradation, and we show that high probabilities of filament nucleation in response to TCR engagement could provide the observed robust, homogeneous, and tunable response dynamic. Furthermore, the speed of autophagic degradation of filaments preferentially at filament ends provides effective regulatory control. Taken together, these data suggest that Bcl10 filament growth and degradation act as an excitable system that provides a digital response mechanism and the reliable timing critical for T cell activation and regulatory processes. Author SummaryThe immune system serves to protect organisms against pathogen-mediated disease. While a strong immune response is needed to eliminate pathogens in host organisms, immune responses that are too robust or too persistent can trigger autoimmune disorders, cancer, and a variety of additional serious human pathologies. Thus, a careful balance of activating and inhibitory mechanisms are necessary to prevent detrimental health outcomes of immune responses. For example, activated effector T cells marshal the immune response and direct killing of pathogen-infected cells; however, effector T cells that are chronically activated can damage and destroy healthy tissue. Here, we study an important internal activation pathway in effector T cells that involves the growth and counterbalancing degradation (via a process called macroautophagy) of filamentous cytoplasmic signaling structures. We utilize image analysis of 3-D super-resolution images and Monte Carlo simulations to study a key signal-transduction protein, Bcl10. We found that the speed of filament degradation has the greatest effect on the magnitude and duration of the response, implying that pharmaceutical interventions aime...

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MyD88 Death-Domain Oligomerization Determines Myddosome Architecture: Implications for Toll-like Receptor Signaling

Cited by 58 publications

References 47 publications

On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

Negative Regulation of TLR Signaling by BCAP Requires Dimerization of Its DBB Domain

Signaling through polymerization and degradation: Analysis and simulations of T cell activation mediated by Bcl10

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