On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

Deliz-Aguirre, Rafael; Cao, Fakun; Gerpott, Fenja Hu; Auevechanichkul, Nichanok; Chupanova, Mariam; Mun, YeVin; Ziska, Elke; Taylor, Marcus J.

doi:10.1101/2020.09.03.280917

Cited by 2 publications

(2 citation statements)

References 42 publications

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“…They did not (not shown). These findings are consistent with evidence that MYD88 exists as an autoinhibited oligomer in cells (59)(60)(61). MYD88 functions to link the activation of TIR-containing Toll-like receptors (TLRs) to DFD-containing effector proteins (62), and accordingly is the only adaptor with both a DFD and a TIR module (Figure 2E).…”

Section: A Central Role Of Supersaturation In Signalosomessupporting

confidence: 89%

Protein supersaturation powers innate immune signaling

Gama

Miller

Lange

et al. 2023

Preprint

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The response of cells to existential threats such as virus invasion often involves semi-crystalline polymerization of certain signaling proteins, but the highly ordered nature of the polymers has no known function. We hypothesized that the undiscovered function is kinetic in nature, emerging from the nucleation barrier to the underlying phase transition, rather than the material polymers themselves. We explored this idea using fluorescence microscopy and Distributed Amphifluoric FRET (DAmFRET) to characterize the phase behavior of all 116 members of the death fold domain (DFD) superfamily, the largest group of putative polymer modules in human immune signaling. A subset of them polymerized in a nucleation-limited manner able to digitize cell state. These were enriched for the highly connected hubs of the DFD protein-protein interaction network. Full-length (F.L) signalosome adaptors retained this activity. We then designed and carried out a comprehensive nucleating interaction screen to map the pathways of signaling through the network. The results recapitulated known signaling pathways including a recently discovered link between the different cell death subroutines of pyroptosis and extrinsic apoptosis. We went on to validate this nucleating interaction in vivo. In the process, we discovered that the inflammasome is powered by constitutive supersaturation of the adaptor protein, ASC, implying that innate immune cells are thermodynamically fated for inflammatory cell death. Finally, we showed that supersaturation in the extrinsic apoptosis pathway commits cells to die, whereas the lack of supersaturation in the intrinsic apoptosis pathway permits cells to recover. Our results collectively suggest that innate immunity comes at the cost of occasional spontaneous cell death, and uncover a physical basis for the progressive nature of age-associated inflammation.

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Section: A Central Role Of Supersaturation In Signalosomessupporting

confidence: 89%

Protein supersaturation powers innate immune signaling

Gama

Miller

Lange

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…But interdomain interactions can also limit nucleation. Recent structural and biochemical evidence suggests a tertiary conformational change may underlie the kinetic barrier for MyD88, an adaptor protein of Toll-like receptor (TLR) signaling ( 57 , 58 , 59 ). MyD88 consists of a DD and TIR joined by a flexible linker.…”

Section: Introductionmentioning

confidence: 99%

Mechanics of a molecular mousetrap—nucleation-limited innate immune signaling

Gama

Miller²,

Halfmann³

2021

Biophysical Journal

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Innate immune responses, such as cell death and inflammatory signaling, are typically switch-like in nature. They also involve ''prion-like'' self-templating polymerization of one or more signaling proteins into massive macromolecular assemblies known as signalosomes. Despite the wealth of atomic-resolution structural information on signalosomes, how the constituent polymers nucleate and whether the switch-like nature of that event at the molecular scale relates to the digital nature of innate immune signaling at the cellular scale remains unknown. In this perspective, we review current knowledge of innate immune signalosome assembly, with an emphasis on structural constraints that allow the proteins to accumulate in inactive soluble forms poised for abrupt polymerization. We propose that structurally encoded nucleation barriers to protein polymerization kinetically regulate the corresponding pathways, which allows for extremely sensitive, rapid, and decisive signaling upon pathogen detection. We discuss how nucleation barriers satisfy the rigorous on-demand functions of the innate immune system but also predispose the system to precocious activation that may contribute to progressive age-associated inflammation.

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On demand MyD88 oligomerization is controlled by IRAK4 during Myddosome signaling

Cited by 2 publications

References 42 publications

Protein supersaturation powers innate immune signaling

Protein supersaturation powers innate immune signaling

Mechanics of a molecular mousetrap—nucleation-limited innate immune signaling

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