Human IFNγ Receptor Cytoplasmic Domain: Expression and Interaction with HuIFNγ

Green, Marino M.; Larkin, Joseph; Subramaniam, Prem S.; Szente, Brian E.; Johnson, Howard M.

doi:10.1006/bbrc.1998.8077

Cited by 18 publications

(5 citation statements)

References 31 publications

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“…Hundreds of patients with these deficiencies have been identified worldwide, with no particular ethnic preponderance, except for a higher frequency of recessive forms in areas with high rates of consanguineous unions (7, 13, 14, 16, 23, 25, 31, 44-53, 56, 75-79). The response to IFN-γ is impaired or abolished in affected cific receptor (68)(69)(70)(71). The predicted truncated protein, if translated and expressed, would therefore probably not be functional (68).…”

Section: Discussionmentioning

confidence: 99%

Inherited human IFN-γ deficiency underlies mycobacterial disease

Kerner

Rosain

Guérin

et al. 2020

Journal of Clinical Investigation

105

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Section: Discussionmentioning

confidence: 99%

Inherited human IFN-γ deficiency underlies mycobacterial disease

Kerner

Rosain

Guérin

et al. 2020

Journal of Clinical Investigation

105

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“…Radioiodination of rIFNγ was performed as previously described [86]. rIFNγ (5 µg at 0.5 µg/µl) was radioiodinated with 5 µl (500 µCi) of Na 125 I (17 mCi/µg, BRIT, India) in the presence of 25 µl of 0.15 M potassium buffer, pH 7.4, and 10 µl chloramine-T (5 mg/ml) for 2 minutes.…”

Section: Methodsmentioning

confidence: 99%

Restoration of IFNγR Subunit Assembly, IFNγ Signaling and Parasite Clearance in Leishmania donovani Infected Macrophages: Role of Membrane Cholesterol

et al. 2011

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Despite the presence of significant levels of systemic Interferon gamma (IFNγ), the host protective cytokine, Kala-azar patients display high parasite load with downregulated IFNγ signaling in Leishmania donovani (LD) infected macrophages (LD-MØs); the cause of such aberrant phenomenon is unknown. Here we reveal for the first time the mechanistic basis of impaired IFNγ signaling in parasitized murine macrophages. Our study clearly shows that in LD-MØs IFNγ receptor (IFNγR) expression and their ligand-affinity remained unaltered. The intracellular parasites did not pose any generalized defect in LD-MØs as IL-10 mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation remained unaltered with respect to normal. Previously, we showed that LD-MØs are more fluid than normal MØs due to quenching of membrane cholesterol. The decreased rigidity in LD-MØs was not due to parasite derived lipophosphoglycan (LPG) because purified LPG failed to alter fluidity in normal MØs. IFNγR subunit 1 (IFNγR1) and subunit 2 (IFNγR2) colocalize in raft upon IFNγ stimulation of normal MØs, but this was absent in LD-MØs. Oddly enough, such association of IFNγR1 and IFNγR2 could be restored upon liposomal delivery of cholesterol as evident from the fluorescence resonance energy transfer (FRET) experiment and co-immunoprecipitation studies. Furthermore, liposomal cholesterol treatment together with IFNγ allowed reassociation of signaling assembly (phospho-JAK1, JAK2 and STAT1) in LD-MØs, appropriate signaling, and subsequent parasite killing. This effect was cholesterol specific because cholesterol analogue 4-cholestene-3-one failed to restore the response. The presence of cholesterol binding motifs [(L/V)-X1–5-Y-X1–5-(R/K)] in the transmembrane domain of IFNγR1 was also noted. The interaction of peptides representing this motif of IFNγR1 was studied with cholesterol-liposome and analogue-liposome with difference of two orders of magnitude in respective affinity (KD: 4.27×10−9 M versus 2.69×10−7 M). These observations reinforce the importance of cholesterol in the regulation of function of IFNγR1 proteins. This study clearly demonstrates that during its intracellular life-cycle LD perturbs IFNγR1 and IFNγR2 assembly and subsequent ligand driven signaling by quenching MØ membrane cholesterol.

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“…To confirm previous publications demonstrating the binding of the SOCS1-KIR mimetic peptide to the autophosphorylation site of pJak2 (Jak2 1001–1013) 23 , 34 , direct and competitive in vitro binding assays were conducted. The direct binding assay showed that biotinylated pJak2 (1001–1013), but not control peptide, bound to plate associated SOCS1-KIR mimetic peptide in a dose dependent manner which was denoted by increased absorbance, yielding a dissociation constant (Kd) of 1.7 μM (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…pJAK2 ( 1001 LPQDKEYYKVKEP) was generated in-house using Applied Biosystems 431a automated peptide synthesizer (Applied Biosystems, Carlsbad, CA) by conventional fluorenylmethylcarbonyl chemical methods as described 34 .…”

Section: Methodsmentioning

confidence: 99%

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Open label safety and efficacy pilot to study mitigation of equine recurrent uveitis through topical suppressor of cytokine signaling-1 mimetic peptide

Plummer

Sharma

Bae

et al. 2022

Sci Rep

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Equine recurrent uveitis (ERU) is a painful and debilitating autoimmune disease and represents the only spontaneous model of human recurrent uveitis (RU). Despite the efficacy of existing treatments, RU remains a leading cause of visual handicap in horses and humans. Cytokines, which utilize Janus kinase 2 (Jak2) for signaling, drive the inflammatory processes in ERU that promote blindness. Notably, suppressor of cytokine signaling 1 (SOCS1), which naturally limits the activation of Jak2 through binding interactions, is often deficient in autoimmune disease patients. Significantly, we previously showed that topical administration of a SOCS1 peptide mimic (SOCS1-KIR) mitigated induced rodent uveitis. In this pilot study, we test the potential to translate the therapeutic efficacy observed in experimental rodent uveitis to equine patient disease. Through bioinformatics and peptide binding assays we demonstrate putative binding of the SOCS1-KIR peptide to equine Jak2. We also show that topical, or intravitreal injection of SOCS1-KIR was well tolerated within the equine eye through physical and ophthalmic examinations. Finally, we show that topical SOCS1-KIR administration was associated with significant clinical ERU improvement. Together, these results provide a scientific rationale, and supporting experimental evidence for the therapeutic use of a SOCS1 mimetic peptide in RU.

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Human IFNγ Receptor Cytoplasmic Domain: Expression and Interaction with HuIFNγ

Cited by 18 publications

References 31 publications

Inherited human IFN-γ deficiency underlies mycobacterial disease

Inherited human IFN-γ deficiency underlies mycobacterial disease

Restoration of IFNγR Subunit Assembly, IFNγ Signaling and Parasite Clearance in Leishmania donovani Infected Macrophages: Role of Membrane Cholesterol

Open label safety and efficacy pilot to study mitigation of equine recurrent uveitis through topical suppressor of cytokine signaling-1 mimetic peptide

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