The innate immune response is an important component of host defense against pathogenic infection. However, different levels of regulatory mechanisms, including post-transcriptional regulation, are needed to elaborately regulate the inflammatory response without causing harmful health effects. A novel terminal uridyltransferase (TUT) is known to control the fate and stability of RNAs by adding uridine tails to their 3' ends, but its exact function in regulating the innate immune response remains elusive. Here, we reveal that TLR4 activation induces this novel TUT expression, which in turn selectively regulates the production of a subset of cytokines, including Interleukin-6 (IL-6). The TUT mediates IL-6 expression by controlling Regnase-1 mRNA stability. Mechanistically, TLR4 activation causes the TUT to bind directly to the stem-loop structure on the 3'UTR of Regnase-1, prompting uridylation and degradation of Regnase-1 mRNA. Consistently, Regnase-1 mRNAs possess uridylated 3' ends and shorter poly(A) tails in TUT-proficient macrophages after TLR4 activation, whereas Regnase-1 transcripts in Tut -/- cells carry long poly(A) tails without uridylation. Together, our findings reveal the functional role of the TUT in sculpting TLR4-driven responses by modulating the mRNA stability of inflammatory mediators.
Date:
2019-10
Relation:
European Journal of Immunology. 2019 Oct;49(S3):42.
