Transient responses via regulation of mRNA stability as an immuno-logical strategy for countering infectious diseases.
Posttranscriptional regulation of gene expression plays a pivotal role as a fast control system for T-cells and B-cells 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.
Nakagawa
Junichi
J
Junichi Nakagawa Department of Food Science and Technology, Faculty of Bio-Industry, Tokyo University of Agriculture, 196 Yasaka, Abashiri-city, Hokkaido 099-2493, Japan. j3nakaga@bioindustry.nodai.ac.jp
D000225:Adenine / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007152:Immunologic Capping / Q000187:drug effects; D007239:Infections / Q000188:drug therapy*; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000890:Anti-Infective Agents; D016207:Cytokines; D012333:RNA, Messenger; D000225:Adenine