Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay

Abstract

Here the zinc finger protein encoded by the Zc3h12a gene is shown to be a ribonuclease with an essential role in modulating innate immune responses. Zc3h12a is inducible by Toll-like receptors, and this new work suggests that it inhibits autoimmune disease by controlling the degradation of mRNAs encoding proinflammatory cytokines. The zinc finger protein Zc3h12a is identified as a ribonuclease that inhibits autoimmune disorders by controlling the degradation of messenger RNAs encoding proinflammatory cytokines. Toll-like receptors (TLRs) recognize microbial components, and evoke inflammation and immune responses1,2,3. TLR stimulation activates complex gene expression networks that regulate the magnitude and duration of the immune reaction. Here we identify the TLR-inducible gene Zc3h12a as an immune response modifier that has an essential role in preventing immune disorders. Zc3h12a-deficient mice suffered from severe anaemia, and most died within 12 weeks. Zc3h12a-/- mice also showed augmented serum immunoglobulin levels and autoantibody production, together with a greatly increased number of plasma cells, as well as infiltration of plasma cells to the lung. Most Zc3h12a-/- splenic T cells showed effector/memory characteristics and produced interferon-γ in response to T-cell receptor stimulation. Macrophages from Zc3h12a-/- mice showed highly increased production of interleukin (IL)-6 and IL-12p40 (also known as IL12b), but not TNF, in response to TLR ligands. Although the activation of TLR signalling pathways was normal, Il6 messenger RNA decay was severely impaired in Zc3h12a-/- macrophages. Overexpression of Zc3h12a accelerated Il6 mRNA degradation via its 3′-untranslated region (UTR), and destabilized RNAs with 3′-UTRs for genes including Il6, Il12p40 and the calcitonin receptor gene Calcr. Zc3h12a contains a putative amino-terminal nuclease domain, and the expressed protein had RNase activity, consistent with a role in the decay of Il6 mRNA. Together, these results indicate that Zc3h12a is an essential RNase that prevents immune disorders by directly controlling the stability of a set of inflammatory genes.