Structures of MyD88 and its oncogenic mutant reveal DNA binding with implications for cytosolic DNA sensing

Cryo-EM structures of MyD88 TIR and its oncogenic L252P mutant show dsDNA binding on ring/spiral concave surfaces, enabling dsDNA-driven inflammatory signaling.

• Why it matters: It is unclear how the MyD88 TIR platform supports signaling and whether MyD88 has additional roles in cytosolic DNA sensing beyond endosomal TLR pathways.
• What they did: The authors solved cryo-EM structures of MyD88TIR and L252P, then used in vitro binding, dsDNA transfection/viral infection in cells, and RNA-seq; they also tested UNC93B1 deficiency and a structure-guided dsDNA-binding–disrupting mutant.
• The result: MyD88 directly binds dsDNA and promotes pro-IL-1{beta} expression after dsDNA delivery or infection, independent of UNC93B1, and a dsDNA-binding–disrupting mutant selectively impairs dsDNA-induced transcription while preserving TLR signaling; about half of cGAS-dependent genes are also MyD88-dependent.

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