The role of mammalian MAPK signaling in regulation of cytokine mRNA stability and translation.
Extracellular-regulated kinases and p38 mitogen-activated protein kinases are activated in innate (and adaptive) immunity and signal via different routes to alter the stability and translation of various cytokine mRNAs, enabling immune cells to respond promptly. This regulation involves mRNA elements, such as AU-rich motifs, and mRNA-binding proteins, such as tristetraprolin (TTP), HuR, and hnRNPK-homology (KH) type splicing regulatory protein (KSRP). Signal-dependent phosphorylation of mRNA-binding proteins often alters their subcellular localization or RNA-binding affinity. Furthermore, it could lead to an altered interaction with other mRNA-binding proteins and altered scaffolding properties for mRNA-modifying enzymes, such as deadenylases, polyadenylases, decapping enzymes, poly(A) binding proteins, exo- or endonucleases, and proteins of the exosome machinery. In many cases, this results in unstable mRNAs being stabilized, with their translational arrest being released and cytokine production being stimulated. Hence, components of these mechanisms are potential targets for the modulation of the inflammatory response.
Institute of Physiological Chemistry, Hannover Medical School , Hannover, Germany.
Christopher
C
Tiedje
Helmut
H
Holtmann
Matthias
M
Gaestel
D056704:Adaptive Immunity; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D051959:ELAV Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008322:Mammals; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000276:immunology; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism; D051816:Tristetraprolin / Q000378:metabolism
D016207:Cytokines; D051959:ELAV Proteins; C105789:KHSRP protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D051816:Tristetraprolin; D048049:Extracellular Signal-Regulated MAP Kinases