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Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation

Author

Listed:
  • Chia-Ching Lin

    (National Taiwan University)

  • Yi-Ru Shen

    (National Taiwan University)

  • Chi-Chih Chang

    (National Taiwan University)

  • Xiang-Yi Guo

    (National Taiwan University)

  • Yun-Yun Young

    (National Taiwan University)

  • Ting-Yu Lai

    (National Taiwan University)

  • I-Shing Yu

    (National Taiwan University)

  • Chih-Yuan Lee

    (National Taiwan University
    National Taiwan University Hospital
    National Taiwan University)

  • Tsung-Hsien Chuang

    (National Health Research Institutes)

  • Hsin-Yue Tsai

    (National Taiwan University
    National Taiwan University)

  • Li-Chung Hsu

    (National Taiwan University
    National Taiwan University)

Abstract

Different levels of regulatory mechanisms, including posttranscriptional regulation, are needed to elaborately regulate inflammatory responses to prevent harmful effects. Terminal uridyltransferase 7 (TUT7) controls RNA stability by adding uridines to its 3′ ends, but its function in innate immune response remains obscure. Here we reveal that TLR4 activation induces TUT7, which in turn selectively regulates the production of a subset of cytokines, including Interleukin 6 (IL-6). TUT7 regulates IL-6 expression by controlling ribonuclease Regnase-1 mRNA (encoded by Zc3h12a gene) stability. Mechanistically, TLR4 activation causes TUT7 to bind directly to the stem-loop structure on Zc3h12a 3′-UTR, thereby promotes Zc3h12a uridylation and degradation. Zc3h12a from LPS-treated TUT7-sufficient macrophages possesses increased oligo-uridylated ends with shorter poly(A) tails, whereas oligo-uridylated Zc3h12a is significantly reduced in Tut7-/- cells after TLR4 activation. Together, our findings reveal the functional role of TUT7 in sculpting TLR4-driven responses by modulating mRNA stability of a selected set of inflammatory mediators.

Suggested Citation

  • Chia-Ching Lin & Yi-Ru Shen & Chi-Chih Chang & Xiang-Yi Guo & Yun-Yun Young & Ting-Yu Lai & I-Shing Yu & Chih-Yuan Lee & Tsung-Hsien Chuang & Hsin-Yue Tsai & Li-Chung Hsu, 2021. "Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24177-7
    DOI: 10.1038/s41467-021-24177-7
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