Transient Responses Via Regulation of mRNA Stability as an Immunological Strategy for Countering Infectious Diseases

Junichi      Nakagawa

Abstract

Posttranscriptional regulation of gene expression plays a pivotal role as a fast control system for T-cells and Bcells operating in the defense reactions against rapidly growing infectious agents. The framework of this machinery involves cis-acting elements in the mRNAs of relevant cytokines and trans-acting factors interacting with these elements. The cis- and trans-acting factors enforce rapid mRNA decay with other proteins such as nucleases in the decay machinery. The most prominent cis-element contains A + U- rich sequence (ARE), and is located in the 3-untranslated region of the target mRNAs. Some ARE-binding proteins promote the rapid decay, and others protect the mRNA from degradation. The 5-end of nascent mRNA undergoes capping which protects the 5-end together with the cap-binding protein, and the 3 end is protected with poly (A) tail and associating poly (A) binding protein. Unlike in classical drawing of linear structure of mRNA, the end structures interact with each other through a common platform composed of translation initiation factors, revealing the cross-talk of the 5-end cap structure and 3-end poly (A) tail on the translational machinery. The rapid degradation and stabilization of mRNA is triggered by a cellular signaling cascade through phosphorylation of associating protein factors in response to environmental stimuli, and a large nucleolytic complex for specific decay reaction called exosome is formed with the 3-UTR of mRNA through interaction with the ARE-binding proteins. Possible therapeutic agents modifying stability of ARE-containing mRNA are being screened in order to treat immunological disorders.

Keywords: Posttranscriptional regulation, ARE, cytokine, AUBP, mRNA decay, hematopoietic differentiation, chemotherapy, exosome