Post‐Natal Growth and Liver Immune Homeostasis are Post‐Transcriptionally Regulated by Tristetraprolin Family of RNA Binding Proteins

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Tristetraprolin family of RNA binding proteins, including tristetraprolin (TTP), zinc finger protein 36 like 1 (ZFP36L1), and zinc finger protein 36 like 2 (ZFP36L2) regulate mRNA levels by binding to AU‐rich elements on the 3′ untranslated regions of specific mRNAs and enhancing their turnover. While the three proteins behave similarly under biochemical conditions, they appear to have diverse physiological functions. This is apparent from the global deletion of the three proteins in mice. While the global loss of TTP results in systemic inflammatory syndrome, global loss of ZFP36L1 is embryonic lethal, and the global loss of ZFP36L2 results in early post‐natal mortality. Here, we sought to understand the physiological functions of the three proteins in liver by conditional liver specific deletion using Cre‐loxP technology. While the independent deletion of the three proteins did not result in any aberrant phenotype, simultaneous deletion resulted in post‐natal growth defect, chronic active portal hepatitis, and bile duct hyperplasia. Transcriptomic analysis showed small numbers of gene expression changes in the liver of ZFP36L1 knockout, no changes in the livers of TTP and ZFP36L2 knockout, and many changes in the liver of mice deleted of the three proteins simultaneously. The changes included perturbation of genes that regulate post‐natal growth and several inflammatory mediators, some of which are novel potential liver‐specific targets of TTP family proteins. Interestingly, one allele of either ZFP36L1 or ZFP36L2 was sufficient to protect the mice from developing this phenotype. However, one allele of TTP was only partially protective. In summary, our results suggest that post‐transcriptional regulation of gene expression plays an important role in post‐natal growth and liver immune homeostasis and that TTP family proteins regulate these physiological functions in both specific and redundant manner.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.