The knockout mouse model reveals the multi-faceted functions of AUF1.

摘要

Regulation of mRNA stability provides a critical control point of gene expression that allows cells to adapt to continuously changing physiological conditions. The rate of degradation of many short-lived mRNAs, including those encoding cytokine and cell cycle regulators, is determined by the interaction of trans-acting binding proteins with cis-acting adenine/uridine-rich element (ARE) in the 3' untranslated region (UTR). Our work aims to characterize the role, cellular targets, and physiological importance of the ARE-binding protein AUF1. Employing AUF1-deficient cells and mice, we demonstrate that AUF1 is important in the regulation of ARE-mediated decay of select proinflammatory cytokine mRNAs, including tumor necrosis factor alpha, lymphotoxin alpha, and interleukin IL-1beta, as well as ARE-mRNAs of cell cycle regulators, p16Ink4A and p21CIP. AUF1 knockout mice exhibit various phenotypes that are associated with deregulation of these mRNAs, including sensitivity to endotoxic shock, poorly organized splenic T and B cell zones, inflammatory skin disease, and accelerated aging. Furthermore, we demonstrate that AUF1 can have both stabilizing and destabilizing functions on the same ARE-containing mRNA targets. We propose a model by which AUF1, in response to environmental cues, is able to adapt its function in mRNA stability to coordinate with vi the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. In addition to its role in ARE-mediated mRNA decay, we demonstrate that AUF1 is a regulator of telomere length maintenance and discuss the effects of this deregulation in AUF1-deficient cells and mice with regard to cellular senescence and tumorigenesis. In conclusion, this work underscores the physiological significance of diverse AUF1 functions in mice and provides insight into the pathobiology of a wide range of associated human diseases, including septic shock, systemic rheumatic diseases, atopic dermatitis, tumorigenesis and limb-girdle muscular dystrophy.