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.1998.8473

Cited by 5 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have identified a high-affinity, species-nonspecific binding site (K d , 10 Ϫ8 M) for the IFN-␥ C terminus on the cytoplasmic domain of both human and murine IFNGR-1 (9). This site, also demonstrable in whole cells, was identified as a membrane proximal region of the cytoplasmic domain within amino acid residues 253 through 287 (13).…”

Section: Discussionmentioning

confidence: 96%

Peptide Mimetics of Gamma Interferon Possess Antiviral Properties against Vaccinia Virus and Other Viruses in the Presence of Poxvirus B8R Protein

Ahmed

Burkhart

Subramaniam

et al. 2005

J Virol

Self Cite

View full text Add to dashboard Cite

We have developed peptide mimetics of gamma interferon (IFN-␥) that play a direct role in the activation and nuclear translocation of STAT1␣ transcription factor. These mimetics do not act through recognition by the extracellular domain of IFN-␥ receptor but rather bind to the cytoplasmic domain of the receptor chain 1, IFNGR-1, and thereby initiate the cellular signaling. Thus, we hypothesized that these mimetics would bypass the poxvirus virulence factor B8R protein that binds to intact IFN-␥ and prevents its interaction with the receptor. Human and murine IFN-␥ mimetic peptides were introduced into an adenoviral vector for intracellular expression. There are several studies using mostly nucleoside analogs to test their efficacy against acute exposure to smallpox and other poxviruses (5,6,17). The most promising of these analogs appears to be cidofovir (5). However, undesirable toxic effects, particularly those involving kidneys, have been observed in animal studies (17). Perhaps this is because these drugs do not appear to be virus specific. Thus, there is a timely need for other approaches to the development of poxvirus therapeutic agents. Vaccinia virus, which is used worldwide to vaccinate against smallpox infections, is a prototype of the poxvirus family. These viruses are particularly effective in neutralizing host innate antiviral defense mechanisms, such as the interferon (IFN) system. A major reason for this is the production by these viruses of soluble secreted proteins that bind to and prevent alpha/beta IFN (IFN-␣/␤) and IFN-␥ from binding to their respective receptors on the cell membrane (16). An important virulence factor of poxviruses is the B8R protein, which is a homolog of the extracellular domain of the IFN-␥ receptor and can therefore bind to intact IFN-␥ and prevent its interaction with the receptor (24).We have discovered, characterized, and synthesized small peptide agonists/mimetics of IFN-␥. These peptides, consisting of IFN-␥ C terminus and C terminus analogs, HuIFN-␥(95-134) (from amino acid 95 to 134) for humans and MuIFN-␥(95-133) (from amino acid 95 to 133) for mice, possess potent antiviral activity against vesicular stomatitis virus (VSV) (25)(26)(27)(28). VSV is commonly used in the detection and quantitation of IFN activity. The structural motif required for the recognition of the extracellular domain of the IFN-␥ receptor chain IFNGR-1 and that involved in intracellular signaling are contained in two separate domains on the N terminus and C terminus, respectively, of the IFN-␥ molecule (28, 31). The peptide mimetics act intracellularly to activate the Jak/STAT signaling apparatus and, thus, do not recognize the IFN-␥ receptor extracellular domain (28). Therefore, smallpox and vaccinia virus virulence factor B8R should not interact with the IFN-␥ mimetics and, thus, should not block mimetic antiviral activity. The mimetics were delivered into the cell via penetration by attachment of a lipophilic residue to chemically synthesized peptides, as described earlier for the deliver...

show abstract

Section: Discussionmentioning

confidence: 96%

Peptide Mimetics of Gamma Interferon Possess Antiviral Properties against Vaccinia Virus and Other Viruses in the Presence of Poxvirus B8R Protein

Ahmed

Burkhart

Subramaniam

et al. 2005

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…The biological activity of intracellular IFN-g required the presence of the IFN-g receptor within the cell [65]. The intracellular activity of IFN-g in macrophages could result from its interaction with the cytosolic domain of the IFN-g receptor [66] or from the delivery of recycling endosomes loaded with IFN-g to newly formed phagocytic vacuoles or autophagosomes that carry fully competent IFN-g receptors in their membranes. Although controversial, such a pathway might operate in activated macrophages that do not release IFN-g [13], build up IFN-g stores in the resting state [14,30] or synthesize as yet undetectable quantities of the protein following activation [25] ( Figure 1d).…”

Section: Intracellular Action Of Ifn-gmentioning

confidence: 99%

Production of interferon-γ by myeloid cells – fact or fancy?

Bogdan

Schleicher

2006

Trends in Immunology

View full text Add to dashboard Cite

“…(13,17) Intracellular microinjection of antibodies to this region has been shown to block signal transduction by extracellular IFN-g. (10) This carboxy-terminus has been shown to interact with the cytoplasmic domain of IFN GR1. (14) We have shown recently that the IFNGRa translocates to the nucleus with kinetics similar to that of Stat1a, a protein activated by IFN-g, suggesting that they in fact comigrate to the nucleus. (11) These data help provide insight into the importance of this NLS-containing carboxy-terminus of IFN-g in induction of IFN-g activity.…”

mentioning

confidence: 94%

“…As we have indicated previously, two putative NLS sequences, 85 KKKR 90 and 127 KRKRS 133 , in HuIFNg have been identified and were the focus of our study. It has been known for some time that the sequence 95-133, which encompasses one of the sequences used in this study, is required and even sufficient for biologic activity, (13) In view of the fact that the carboxyl-terminal region of IFN-g interacts with the cytoplasmic domain of the IFNGR1 chain in a species-nonspecific manner, (14) a functional NLS within this region of IFN-g would provide insight into its intracellular biologic activity.…”

Section: Introductionmentioning

confidence: 99%

Differential Properties of Two Putative Nuclear Localization Sequences Found in the Carboxyl-Terminus of Human IFN-γ

Larkin

Subramaniam²,

Torres³

et al. 2001

Journal of Interferon & Cytokine Research

Self Cite

View full text Add to dashboard Cite

Interferon-gamma (IFN-gamma), a protein that uses the Jak-Stat pathway for signal transduction, translocates rapidly to the nucleus in cells treated extracellularly with the cytokine. A nuclear localization sequence (NLS) has been identified and characterized in the C-terminus of IFN-gamma. Both human and murine IFN-gamma contain this NLS. We show in this report that human IFN-gamma (HuIFN-gamma) contains a second NLS at an upstream site, as determined in standard import assays using digitonin-permeabilized HeLa cells. The primary sequence, analogous with the NLS sequence identified in murine IFN-gamma, representing amino acids 122-132 of HuIFN-gamma was capable of mediating the nuclear import of the autofluorescent protein allophycocyanin (APC) in an energy-dependent manner. The second sequence, representing amino acids 78-92 of HuIFN-gamma, was also capable of mediating the nuclear import of APC in an energy-dependent manner but to a greatly reduced extent. The nuclear import of both sequences conjugated to APC was strongly blocked by competition with unconjugated HuIFN-gamma(122-132). Competition by the sequence HuIFN-gamma(78-92) effectively blocked the import of APC-conjugated HuIFN-gamma(78-92) but, at the same concentration, was not capable of inhibiting the nuclear import of APC-conjugated HuIFN-gamma(122-132), suggesting that HuIFN-gamma(78-92) was a less efficient NLS than HuIFN-gamma(122-132). This is consistent with >90% loss of antiviral activity of HuIFN-gamma lacking the downstream NLS in 122-132. The nuclear import of APC-conjugated HuIFN-gamma(122-132) was inhibited by a peptide containing the prototypical polybasic NLS of the SV40 T NLS, which suggests that the same Ran/importin cellular machinery is used in both cases.

show abstract

Human IFNγ Receptor Cytoplasmic Domain: Expression and Interaction with HuIFNγ

Cited by 5 publications

References 0 publications

Peptide Mimetics of Gamma Interferon Possess Antiviral Properties against Vaccinia Virus and Other Viruses in the Presence of Poxvirus B8R Protein

Peptide Mimetics of Gamma Interferon Possess Antiviral Properties against Vaccinia Virus and Other Viruses in the Presence of Poxvirus B8R Protein

Production of interferon-γ by myeloid cells – fact or fancy?

Differential Properties of Two Putative Nuclear Localization Sequences Found in the Carboxyl-Terminus of Human IFN-γ

Contact Info

Product

Resources

About