Identification of a STAT4 Binding Site in the Interleukin-12 Receptor Required for Signaling

Naeger, Lisa K.; McKinney, Judi; Salvekar, Anupama; Hoey, Timothy

doi:10.1074/jbc.274.4.1875

Cited by 63 publications

(40 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For IFN-, STAT4 phosphorylation was not affected by the mutations that abolish STAT2 activation, indicating that STAT4 is activated by a STAT2-independent mechanism. Moreover, STAT4 was still activated by a tyrosine-less IL-28R/LICR2, contrasting with the activation of this factor by IL-12, which involved a YLPSNID motif of the IL-12R␤2 chain (26). Thus, STAT4 activation by IFN-might result from a third mechanism of recruitment and activation that deserves further investigation.…”

Section: Ifn-1/il-28r Signaling Mechanismsmentioning

confidence: 86%

Role of the Interleukin (IL)-28 Receptor Tyrosine Residues for Antiviral and Antiproliferative Activity of IL-29/Interferon-λ1

Dumoutier

Tounsi

Michiels

et al. 2004

Journal of Biological Chemistry

278

232

View full text Add to dashboard Cite

Interferon (IFN)-1, -2, and -3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R␤, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/ LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-s and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.The interleukin-28 receptor (IL-28R, also named LICR2 and CRF2-12) 1 is a member of the class II cytokine receptor family (CRF2) (1-3), which includes receptors for type I and type II IFNs (IFNAR1, IFNAR2, IFNGR1, and IFNGR2), tissue factor, and receptors for IL-10-related cytokines: IL-10R␣, IL-22R/ CRF2-9, IL-10R␤/CRF2-4, IL-20R␣/CRF2-8, IL-20R␤/CRF2-11, and IL-28R/LICR2 (4 -7). When IL-28R associates with IL-10R␤, it creates a high affinity binding complex for IFN-1, -2, and -3 (also called IL-29, IL-28a, and IL-28b) (2, 3). These cytokines share limited sequence similarity with type I IFNs. Like type I IFNs, they are expressed by human peripheral blood mononuclear cells and dendritic cells upon infection with viruses or stimulation with poly(I:C) (2, 3, 8).Although they use distinct receptor chains, which have no detectable homology in their intra-cytoplasmic domain, type I IFNs and IFN-s activate similar signal transduction pathways. Chimeric receptors containing the intracellular portion of IL-28R/LICR2 could mediate JAK1 (Janus kinase 1) activation, as well as tyrosine phosphorylation of STAT factors (1, 2), including STAT2, whose activation was considered to be a specific characteristic of the type I IFN response (9, 10).Most importantly, IFN-1, -2, and -3 protected several cell lines against viral infection and up-regulated major histocompatibility complex class I antigen expression (2, 3). Receptors for type I IFNs are composed of two chains, IFNAR1 and IFNAR2, in which 3 tyrosines seem to be essential to recruit STAT2: Tyr 466 in IFNAR1, and Tyr 337 and Tyr 512 in IFNAR2 (11, 12). Here, we introduced point mutations into the cytoplasmic domain of IL-28R/LICR2 to determine which tyrosines are involved in different ...

show abstract

Section: Ifn-1/il-28r Signaling Mechanismsmentioning

confidence: 86%

Role of the Interleukin (IL)-28 Receptor Tyrosine Residues for Antiviral and Antiproliferative Activity of IL-29/Interferon-λ1

Dumoutier

Tounsi

Michiels

et al. 2004

Journal of Biological Chemistry

278

232

View full text Add to dashboard Cite

show abstract

“…In this report, we demonstrate an important difference between Stat4 activation by the IL-12 and IFN-␣ signaling pathways. In IL-12 signaling, Stat4 is recruited directly to the receptor complex by the cytoplasmic domain of the IL-12R ␤2 subunit (18). In contrast, in IFN-␣ signaling, Stat4 is not recruited directly to the receptor but appears to be indirectly recruited through an intermediate involving activated Stat2.…”

Section: Stat4 Activation Is Involved In Differentiation Of Type 1 Hementioning

confidence: 99%

Recruitment of Stat4 to the Human Interferon-α/β Receptor Requires Activated Stat2

Farrar¹,

Smith

Murphy

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Lymphocytes from STAT4 knockout mice are unable to produce sufficient IFN-␥, proliferate, and lyse target cells in response to IL-12 (19,20). Cells reconstituted with the high-affinity IL-12R␤1/IL-12R␤2 plus various STATs are able to activate only STAT4 when stimulated with IL-12 (13). In addition, CD4 T cells from STAT4 knockout mice bearing an IL-12R␤2 chain transgene are unable to exhibit IL-12-mediated IFN-␥ production (16).…”

mentioning

confidence: 99%

“…Both chains are essential for the high affinity binding of IL-12 to its receptor (10). STAT4 resides in the cytoplasm as a monomer in resting states, but after activation with IL-12 (11,12) it is recruited to a tyrosine-based motif in the IL-12R␤2 chain via the STAT4 Src homology 2 domain (13). After tyrosine phosphorylation, STAT4 forms a homodimer via reciprocal interaction through conserved Src homology 2 domains, and then the STAT4 dimer translocates to the nucleus where it regulates the transcription of IFN-␥ (11, 12, 14 -16).…”

mentioning

confidence: 99%

Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection

Toyoda

Ido

Hayashi

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

We examined the immunological abnormality in a patient with recurrent Mycobacterium avium infection. T cells from the patient showed decreased ability both to produce IFN-γ and to proliferate in response to IL-12. Despite decreased expression of IL-12R β1 and β2 chains in the patient’s PHA-activated T cells, there was no difference in IL-12-induced tyrosine and serine phosphorylation of STAT4 in PHA-activated T cells between the patient and healthy subjects, suggesting that IL-12R signals are transmitted to STAT4 in the patient’s PHA-activated T cells. Using EMSA, confocal laser microscopy, and Western blotting, we demonstrated that the nuclear translocation of STAT4 in response to IL-12 is reduced in PHA-activated T cells from the patient when compared with those from healthy subjects. Leptomycin B was used to examine whether nuclear export of STAT4 is increased in the patient’s T cells. However, leptomycin B treatment did not reverse impaired IL-12-induced nuclear accumulation of STAT4. Although the exact mechanism responsible for the impaired STAT4 nuclear translocation in this patient remains unclear, the absence of mutation in the IL-12Rβ1, IL-12Rβ2, STAT4, and STAT4-binding sequence of the IFN-γ gene and preservation of STAT4 tyrosine and serine phosphorylation suggest the existence of a defective STAT4 nuclear translocation. This defect is likely responsible for the impaired STAT4 nuclear translocation in IL-12-stimulated T cells, leading to impairment of both IFN-γ production and cell proliferation. To the best of our knowledge, this is the first report of a patient with atypical mycobacterial infection associated with impairment of STAT4 nuclear translocation.

show abstract

Identification of a STAT4 Binding Site in the Interleukin-12 Receptor Required for Signaling

Cited by 63 publications

References 36 publications

Role of the Interleukin (IL)-28 Receptor Tyrosine Residues for Antiviral and Antiproliferative Activity of IL-29/Interferon-λ1

Role of the Interleukin (IL)-28 Receptor Tyrosine Residues for Antiviral and Antiproliferative Activity of IL-29/Interferon-λ1

Recruitment of Stat4 to the Human Interferon-α/β Receptor Requires Activated Stat2

Impairment of IL-12-Dependent STAT4 Nuclear Translocation in a Patient with Recurrent Mycobacterium avium Infection

Contact Info

Product

Resources

About