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

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. Terminal uridyltransferase 7 (TUT7) adds U-tails on diverse RNAs to promote degradation. Here the authors show that TUT7 is induced upon LPS treatment in macrophages and promotes decay of Regnase-1, thereby regulating the expression of a subset of cytokines, including IL-6.

Automated summary

TUT7 is induced upon TLR4 activation in macrophages and plays a key role in sculpting inflammatory responses by modulating mRNA stability of selected inflammatory mediators, such as IL-6.