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.
Highlights
Inflammatory cytokines and chemokines are mediators of inflammation in the innate arm of immunity
We reveal that TLR4 activation in macrophages upregulates Terminal uridyltransferase 7 (TUT7) expression and TUT7 selectively regulates the expression of a subset of inflammatory cytokines
We discovered that LPS treatment dramatically increased TUT7 expression in bone marrow-derived macrophages (BMDMs) (Fig. 1a)
Summary
Inflammatory cytokines and chemokines are mediators of inflammation in the innate arm of immunity. Innate cells produce inflammatory cytokines and chemokines rapidly upon infection or tissue injury through an array of patternrecognition receptors (PRRs)[1]. Amongst all PRR families, Toll-like receptors (TLRs) are the most wellcharacterized and they play an important role in innate immune responses[2]. (TBK1)/interferon regulatory factor 3 (IRF3) for the production of pro-inflammatory cytokines/chemokines and type I interferons, respectively[4,5]. Inflammatory responses induced by TLRs or other PRRs are controlled by layers of regulatory mechanisms including: modulation of signaling transduction, posttranscriptional regulation (PTR), and posttranslational modification (PTM)[6,7]. The role of PTR in regulation of PRR-triggered inflammatory response has come to light as of late. Cytokine mRNAs are subject to various regulatory cis-elements in their 3′-
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