Under nutrient replete conditions, mTORC1 promotes anabolic, biosynthetic and proliferative pathways, including protein, lipid and nucleotide synthesis that are required for cell growth 18. ![]() mTORC1 activation requires binary inputs from growth factor-induced Akt-mediated signaling that activates mTOR, and repletion of intracellular amino acids, which enables translocation of mTORC1 to lysosomal membranes where mTOR activation occurs 18. mTORC1 senses and coordinates cellular responses to the nutrient status of extracellular and intracellular microenvironments, and is regulated by growth factors, oxygen, stress, and intracellular amino acid and energy levels. The mechanistic target of rapamycin (mTOR) serine threonine kinase is a component of distinct mTORC1 and mTORC2 complexes, of which mTORC1 is an important regulator of mRNA translation 18. Little is known about regulation of translation by IFN-γ in immune cells. IFNs can promote translation of ISGs by various mechanisms 16, and IFN-γ suppresses translation of a small set of mRNAs 17. ![]() Type I IFNs suppress translation 13 by inactivating translation factor eIF2α 14 and inducing ISGs that translationally silence viral RNAs 15. eIF4E activity is regulated by MNK kinases and mechanistic target of rapamycin complex 1 (mTORC1) 7, and thus is responsive to upstream signals that activate MAPK signaling or mTORC1 activity. Although eIF4E is a general translation initiation factor, changes in its activity do not globally regulate translation but instead selectively affect translation of a subset of transcripts, including inefficiently translated transcripts with long 5’ untranslated regions (UTRs) 7, 11, 12. Selective translational regulation of mRNA transcripts typically occurs at the level of initiation and can be achieved by specific RNA-binding proteins, microRNAs, and by modulation of the activity of 5’ cap-binding eukaryotic initiation factor 4E (eIF4E) 7. Increased translation of select cytokine, chemokine and transcription factor mRNAs has been observed after TLR stimulation 8, 9, and key immune regulators such as I-κBα and IRF7 are under translational control 10, 11. The importance of translational control of immune responses is increasingly appreciated 7. Whether IFN-γ can reprogram macrophage metabolism to alter cell function remains to be elucidated. In parallel, IFN-γ reprograms the ‘epigenetic landscape’ of macrophages by inducing and priming enhancers to increase transcriptional output in response to TLR signaling 5, 6. For example, IFN-γ- augments macrophage cytokine production in response to inflammatory stimuli such as TLR ligands 1 by attenuating signaling via the suppressive transcription factor STAT3 3, and by inhibiting expression of the TLR-induced Notch-dependent transcriptional repressors HES1 and HEY1 4. It has become clear that many IFN-γ activities can not be explained by the direct effector functions of ISGs, and that important IFN-γ functions are mediated by crossregulation of distinct signaling pathways or reprogramming of cell states to alter their responses to extracellular stimuli 1. Direct and rapid activation of ISGs plays a key role in IFN-γ-mediated functions 2. Immune cell activation by IFN-γ is entirely dependent on its activation of the transcription factor STAT1, which binds to and activates transcription of interferon-stimulated genes (ISGs) 2. ![]() ![]() Interferon-γ (IFN-γ) activates innate responses by augmenting inflammatory cytokine and chemokine production, microbial killing, and antigen presentation by mononuclear phagocytes such as macrophages 1.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |