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IFN signaling: how a non-canonical model led to the development of IFN mimetics.

Johnson HM, Noon-Song EN, Dabelic R, Ahmed CM - Front Immunol (2013)

Bottom Line: We have shown that ligand, receptor, activated JAKs, and STATs are associated with specific gene activation, where the receptor subunit IFNGR1 functions as a co-transcription factor and the JAKs are involved in associated epigenetic events.We found that the type I IFN system functions similarly.The non-canonical model could also provide better understanding to more complex cytokine families such as those of IL-2 and IL-12, whose members often use the same JAKs and STATs, but also have different functions and properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA.

ABSTRACT
The classical model of cytokine signaling dominates our view of specific gene activation by cytokines such as the interferons (IFNs). The importance of the model extends beyond cytokines and applies to hormones such as growth hormone (GH) and insulin, and growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF). According to this model, ligand activates the cell via interaction with the extracellular domain of the receptor. This results in activation of receptor or receptor-associated tyrosine kinases, primarily of the Janus activated kinase (JAK) family, phosphorylation and dimerization of the signal transducer and activator of transcription (STAT) transcription factors, which dissociate from the receptor cytoplasmic domain and translocate to the nucleus. This view ascribes no further role to the ligand, JAK kinase, or receptor in either specific gene activation or the associated epigenetic events. The presence of dimeric STATs in the nucleus essentially explains it all. Our studies have resulted in the development of a non-canonical, more complex model of IFNγ signaling that is akin to that of steroid hormone (SH)/steroid receptor (SR) signaling. We have shown that ligand, receptor, activated JAKs, and STATs are associated with specific gene activation, where the receptor subunit IFNGR1 functions as a co-transcription factor and the JAKs are involved in associated epigenetic events. We found that the type I IFN system functions similarly. The fact that GH receptor, insulin receptor, EGF receptor, and FGF receptor undergo nuclear translocation upon ligand binding suggests that they may also function similarly. The SH/SR nature of type I and II IFN signaling provides insight into the specificity of signaling by members of cytokine families. The non-canonical model could also provide better understanding to more complex cytokine families such as those of IL-2 and IL-12, whose members often use the same JAKs and STATs, but also have different functions and properties.

No MeSH data available.


Related in: MedlinePlus

The classical and non-canonical models of IFNγ signaling. (A) In the classical model of IFNγ signaling, dimeric IFNγ cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1α. The dimeric STAT1α dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation. (B) The non-canonical model of IFNγ signaling involves IFNγ binding to receptor extracellular domain, followed by movement to IFNGR1 cytoplasmic domain in conjunction with endocytosis. The cytoplasmic binding increases the affinity of JAK2 for IFNGR1, which is the basis for its movement to IFNGR1. This results in autoactivation of the JAKs, phosphorylation of IFNGR1 cytoplasmic domain, and the binding and phosphorylation of STAT1α at IFNGR1. The complex of IFNGR1/STAT1α/JAK1/JAK2 undergoes active nuclear transport where the classic polycationic NLS of IFNγ plays a key role for this transport to genes in the nucleus that are specifically activated by IFNγ. Details of the non-canonical model are presented in the text. GAS, IFN gamma activated sequence; H3, histone H3; NPC, Nuclear pore complex.
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Figure 1: The classical and non-canonical models of IFNγ signaling. (A) In the classical model of IFNγ signaling, dimeric IFNγ cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1α. The dimeric STAT1α dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation. (B) The non-canonical model of IFNγ signaling involves IFNγ binding to receptor extracellular domain, followed by movement to IFNGR1 cytoplasmic domain in conjunction with endocytosis. The cytoplasmic binding increases the affinity of JAK2 for IFNGR1, which is the basis for its movement to IFNGR1. This results in autoactivation of the JAKs, phosphorylation of IFNGR1 cytoplasmic domain, and the binding and phosphorylation of STAT1α at IFNGR1. The complex of IFNGR1/STAT1α/JAK1/JAK2 undergoes active nuclear transport where the classic polycationic NLS of IFNγ plays a key role for this transport to genes in the nucleus that are specifically activated by IFNγ. Details of the non-canonical model are presented in the text. GAS, IFN gamma activated sequence; H3, histone H3; NPC, Nuclear pore complex.

Mentions: The classical model of JAK/STAT signaling for IFNγ is illustrative of the weight that it puts upon the STATs in specific gene activation (Figure 1A). The heterodimeric receptor subunits are IFNGR1 and IFNGR2, respectively (7, 20, 21). An asymmetric dimer of IFNγ binds predominantly to and cross-links the extracellular domains of two IFNGR1 chains. The model contends that the cross-linking initiates allosteric changes in receptor cytoplasmic domains that are responsible for subsequent events. JAK1 is associated with IFNGR1, whereas JAK2 is associated with IFNGR2. The extracellular binding of IFNγ to IFNGR1 is somehow responsible for the movement of JAK2 from IFNGR2 to IFNGR1, where a sequence of events causes autophosphorylation of the JAKs and tyrosine phosphorylation of IFNGR1, followed by recruitment and phosphorylation of STAT1α (pSTAT1α) at IFNGR1. According to the model, pSTAT1α forms a dimer, dissociates from IFNGR1 and goes to the nucleus via an intrinsic nuclear localization sequence (NLS).


IFN signaling: how a non-canonical model led to the development of IFN mimetics.

Johnson HM, Noon-Song EN, Dabelic R, Ahmed CM - Front Immunol (2013)

The classical and non-canonical models of IFNγ signaling. (A) In the classical model of IFNγ signaling, dimeric IFNγ cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1α. The dimeric STAT1α dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation. (B) The non-canonical model of IFNγ signaling involves IFNγ binding to receptor extracellular domain, followed by movement to IFNGR1 cytoplasmic domain in conjunction with endocytosis. The cytoplasmic binding increases the affinity of JAK2 for IFNGR1, which is the basis for its movement to IFNGR1. This results in autoactivation of the JAKs, phosphorylation of IFNGR1 cytoplasmic domain, and the binding and phosphorylation of STAT1α at IFNGR1. The complex of IFNGR1/STAT1α/JAK1/JAK2 undergoes active nuclear transport where the classic polycationic NLS of IFNγ plays a key role for this transport to genes in the nucleus that are specifically activated by IFNγ. Details of the non-canonical model are presented in the text. GAS, IFN gamma activated sequence; H3, histone H3; NPC, Nuclear pore complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 1: The classical and non-canonical models of IFNγ signaling. (A) In the classical model of IFNγ signaling, dimeric IFNγ cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1α. The dimeric STAT1α dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation. (B) The non-canonical model of IFNγ signaling involves IFNγ binding to receptor extracellular domain, followed by movement to IFNGR1 cytoplasmic domain in conjunction with endocytosis. The cytoplasmic binding increases the affinity of JAK2 for IFNGR1, which is the basis for its movement to IFNGR1. This results in autoactivation of the JAKs, phosphorylation of IFNGR1 cytoplasmic domain, and the binding and phosphorylation of STAT1α at IFNGR1. The complex of IFNGR1/STAT1α/JAK1/JAK2 undergoes active nuclear transport where the classic polycationic NLS of IFNγ plays a key role for this transport to genes in the nucleus that are specifically activated by IFNγ. Details of the non-canonical model are presented in the text. GAS, IFN gamma activated sequence; H3, histone H3; NPC, Nuclear pore complex.
Mentions: The classical model of JAK/STAT signaling for IFNγ is illustrative of the weight that it puts upon the STATs in specific gene activation (Figure 1A). The heterodimeric receptor subunits are IFNGR1 and IFNGR2, respectively (7, 20, 21). An asymmetric dimer of IFNγ binds predominantly to and cross-links the extracellular domains of two IFNGR1 chains. The model contends that the cross-linking initiates allosteric changes in receptor cytoplasmic domains that are responsible for subsequent events. JAK1 is associated with IFNGR1, whereas JAK2 is associated with IFNGR2. The extracellular binding of IFNγ to IFNGR1 is somehow responsible for the movement of JAK2 from IFNGR2 to IFNGR1, where a sequence of events causes autophosphorylation of the JAKs and tyrosine phosphorylation of IFNGR1, followed by recruitment and phosphorylation of STAT1α (pSTAT1α) at IFNGR1. According to the model, pSTAT1α forms a dimer, dissociates from IFNGR1 and goes to the nucleus via an intrinsic nuclear localization sequence (NLS).

Bottom Line: We have shown that ligand, receptor, activated JAKs, and STATs are associated with specific gene activation, where the receptor subunit IFNGR1 functions as a co-transcription factor and the JAKs are involved in associated epigenetic events.We found that the type I IFN system functions similarly.The non-canonical model could also provide better understanding to more complex cytokine families such as those of IL-2 and IL-12, whose members often use the same JAKs and STATs, but also have different functions and properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Cell Science, University of Florida , Gainesville, FL , USA.

ABSTRACT
The classical model of cytokine signaling dominates our view of specific gene activation by cytokines such as the interferons (IFNs). The importance of the model extends beyond cytokines and applies to hormones such as growth hormone (GH) and insulin, and growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF). According to this model, ligand activates the cell via interaction with the extracellular domain of the receptor. This results in activation of receptor or receptor-associated tyrosine kinases, primarily of the Janus activated kinase (JAK) family, phosphorylation and dimerization of the signal transducer and activator of transcription (STAT) transcription factors, which dissociate from the receptor cytoplasmic domain and translocate to the nucleus. This view ascribes no further role to the ligand, JAK kinase, or receptor in either specific gene activation or the associated epigenetic events. The presence of dimeric STATs in the nucleus essentially explains it all. Our studies have resulted in the development of a non-canonical, more complex model of IFNγ signaling that is akin to that of steroid hormone (SH)/steroid receptor (SR) signaling. We have shown that ligand, receptor, activated JAKs, and STATs are associated with specific gene activation, where the receptor subunit IFNGR1 functions as a co-transcription factor and the JAKs are involved in associated epigenetic events. We found that the type I IFN system functions similarly. The fact that GH receptor, insulin receptor, EGF receptor, and FGF receptor undergo nuclear translocation upon ligand binding suggests that they may also function similarly. The SH/SR nature of type I and II IFN signaling provides insight into the specificity of signaling by members of cytokine families. The non-canonical model could also provide better understanding to more complex cytokine families such as those of IL-2 and IL-12, whose members often use the same JAKs and STATs, but also have different functions and properties.

No MeSH data available.


Related in: MedlinePlus