Research highlights

Innate immunity: Targeting the messenger

Nature Reviews Immunology 9, 5 (01 May 2009) | doi:10.1038/nri2552

The authors looked for TLR-inducible genes by comparing microarray data of lipopolysaccharide (LPS)-stimulated macrophages from wild-type mice and from mice lacking the TLR adaptor proteins MyD88 (myeloid differentiation primary-response gene 88) or TRIF (TIR-domain-containing adaptor protein inducing IFN; also known as TICAM1). Zc3h12a was part of a large cluster of genes the expression of which was rapidly induced by TLR signalling in a MyD88-dependent manner. Zc3h12a^-/- mice were generated to investigate the function of this gene; most of the mice died within 12 weeks of birth with severe splenomegaly and lymphadenopathy involving plasma cell accumulation, high levels of serum immunoglobulins (including autoantibodies) and the formation of macrophage granulomas. They concluded that ZC3H12A has an essential role in preventing immune disorders that are characterized by plasma cell and macrophage abnormalities.

Zc3h12a^-/- macrophages stimulated with LPS had increased levels of Il6 (interleukin-6) mRNA and increased production of IL-6 and IL-12p40 compared with wild-type macrophages, but comparable expression of most other LPS-inducible genes. There was no difference in LPS-mediated activation of nuclear factor-B or activator protein 1 between wild-type and Zc3h12a^-/- macrophages, indicating that ZC3H12A is not involved in regulating the initial TLR signalling pathway.

ZC3H12A is a CCCH-type zinc finger protein, other examples of which have been implicated in mRNA decay. In line with this, the half-life of Il6 mRNA was increased in Zc3h12a^-/- macrophages compared with wild-type macrophages, and overexpression of ZC3H12A markedly accelerated the degradation of Il6 mRNA in a tetracycline-responsive system that was used to turn off Il6 transcription. The 3' untranslated region (UTR) of Il6 mRNA was necessary for the effect of ZC3H12A on the rate of degradation, specifically a 30-nucleotide region of the 3' UTR that is conserved between species. Addition of this conserved element to the 3' UTR of -globin conferred sensitivity to ZC3H12A-mediated degradation. Such degradation was shown to require the amino-terminal domain of ZC3H12A, which has RNase activity for the Il6 3' UTR.

These results show that ZC3H12A functions as an immune response modifier downstream of TLR signalling by regulating the longevity of the transcriptional response. Given that 60 CCCH-type zinc finger proteins have been identified in the mammalian genome, each of which seems to have target mRNA specificity, Akira and colleagues suggest that controlling mRNA decay might be a widespread mechanism to regulate immune responses.

Author: Kirsty Minton