Promotion of TLR7-MyD88-dependent inflammation and autoimmunity in mice through stem-loop changes in Lnc-Atg16l1

Zongheng Yang, Shuchen Ji, Lun Liu, Shuo Liu, Bingjing Wang, Yuanwu Ma and Xuetao Cao ()
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Zongheng Yang: Chinese Academy of Medical Sciences
Shuchen Ji: Chinese Academy of Medical Sciences
Lun Liu: Chinese Academy of Medical Sciences
Shuo Liu: Chinese Academy of Medical Sciences
Bingjing Wang: Chinese Academy of Medical Sciences
Yuanwu Ma: Chinese Academy of Medical Sciences
Xuetao Cao: Chinese Academy of Medical Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Uncontrolled TLR signaling can cause inflammatory immunopathology and trigger autoimmune diseases. For example, TLR7 promotes pathogenesis of systemic lupus erythematosus. However, whether RNA structural changes affect nucleic acids-sensing TLRs signaling and impact disease progression is unclear. Here by iCLIP-seq we identify a TLR7-binding long non-coding RNA, Lnc-Atg16l1, and find that it promotes TLR7 and other MyD88-dependent TLRs signaling in various types of immune cells. Depletion of Lnc-Atg16l1 attenuates development of TLR7-linked autoimmune phenotypes in the mouse SLE model. Mechanistically, we find that Lnc-Atg16l1 binds to TLR7 at bases near U84 and MyD88 at bases around A129. The analysis of Lnc-Atg16l1 in situ structures show that it strengthens the interaction between TIR domain of TLR7 and MyD88 through specific stem-loop structure changes as a molecular scaffold after TLR7 activation to promote TLR7 downstream signaling. Therefore, we discover a mechanism for host RNA regulation of innate signaling and autoimmune disease through its structural changes. These findings provide insights into the pro-inflammatory function of self RNA in a structure-dependent manner and suggest a potential target for TLR-related autoimmune disorders.

Date: 2024
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DOI: 10.1038/s41467-024-54674-4

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