EVIDENCE THAT HAX-1 IS AN INTERLEUKIN-1α N-Terminal BINDING PROTEIN

Yin, Han; Morioka, Hideo; Towle, Christine A.; Vidal, Marc; Watanabe, Takeshi; Weissbach, Lawrence

doi:10.1006/cyto.2001.0891

Cited by 38 publications

(40 citation statements)

References 80 publications

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“…Also using the two-hybrid method, ppIL-1␣ has been shown to associate with HAX-1 (30). HAX-1 contains amino acid motifs for binding to several intracellular proteins including polycystin-2 (a protein linked to polycystic kidney disease), cortactin, and Epstein-Barr virus nuclear antigen leader protein (30). We also reported HAX-1 association with the pIL-1␣ in the yeast two-hybrid system.…”

Section: Discussionmentioning

confidence: 66%

“…In mammalian cells pIL-1␣ can associate with necdin to reverse its negative effect on cell growth and production of procollagen (29). Also using the two-hybrid method, ppIL-1␣ has been shown to associate with HAX-1 (30). HAX-1 contains amino acid motifs for binding to several intracellular proteins including polycystin-2 (a protein linked to polycystic kidney disease), cortactin, and Epstein-Barr virus nuclear antigen leader protein (30).…”

Section: Discussionmentioning

confidence: 99%

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The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Werman

Werman-Venkert

White

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

335

283

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Although most cytokines are studied for biological effects after engagement of their specific cell surface membrane receptors, increasing evidence suggests that some function in the nucleus. In the present study, the precursor form of IL-1␣ was overexpressed in various cells and assessed for activity in the presence of saturating concentrations of IL-1 receptor antagonist to prevent receptor signaling. Initially diffusely present in the cytoplasm of resting cells, IL-1␣ translocated to the to nucleus after activation by endotoxin, a Toll-like receptor ligand. The IL-1␣ precursor, but not the C-terminal mature form, activated the transcriptional machinery in the GAL4 system by 90-fold; a 50-fold increase was observed using only the IL-1␣ propiece, suggesting that transcriptional activation was localized to the N terminus where the nuclear localization sequence resides. Under conditions of IL-1 receptor blockade, intracellular overexpression of the precursor and propiece forms of IL-1␣ were sufficient to activate NF-B and AP-1. Stable transfectants overproducing precursor IL-1␣ released the cytokines IL-8 and IL-6 but also exhibited a significantly lower threshold of activation to subpicomolar concentrations of tumor necrosis factor ␣ or IFN-␥. Thus, intracellular functions of IL-1␣ might play an unforeseen role in the genesis of inflammation. During disease-driven events, the cytosolic precursor moves to the nucleus, where it augments transcription of proinflammatory genes. Because this mechanism of action is not affected by extracellular inhibitors, reducing intracellular functions of IL-1␣ might prove beneficial in some inflammatory conditions.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Werman

Werman-Venkert

White

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

335

283

View full text Add to dashboard Cite

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“…The original vector contains Myc and His tags downstream of the cloned cDNA, therefore, all the IL-1␣ proteins were expressed as double tagged chimeras with N-terminal FLAG and C-terminal Myc and His tags. Fragments encoding human deletion mutants IL-1NTP-VVATN (internal deletion aa 78 -87), IL-1NTP-EDSSS (terminal deletion aa [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and IL-1NTP-ITDDD (terminal deletion aa 96 -111) were amplified and cloned into BamHI and XhoI sites of modified pcDNA4/TO/MycHis (see above) vector.…”

Section: Methodsmentioning

confidence: 99%

“…Stevenson et al (14) have shown that IL-1NTP overexpressed in mouse 3T3 fibroblasts behaves as a nuclear oncoprotein and induces their transformation (14). IL-1NTP was also found to be specifically associated with the novel protein HAX-1 that has been implicated in modulating apoptosis and cytoskeletal functions (15). Recently, a strong proapoptotic effect of ectopically expressed IL-1NTP in numerous human tumor cell lines has been reported (16).…”

mentioning

confidence: 99%

Intracellular Interleukin-1α Functionally Interacts with Histone Acetyltransferase Complexes

Buryskova

Pospíšek

Grothey

et al. 2004

Journal of Biological Chemistry

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Interleukin-1␣ (IL-1␣) is an inflammatory cytokine acting extracellularly via membrane receptors. Interestingly, a significant portion of synthesized IL-1␣ is not secreted; instead, it is actively translocated into the cell nucleus. IL-1␣ was indeed shown to be involved in certain intracellular processes, such as control of proliferation, apoptosis, or migration, however, the mechanisms of such actions are not known. Here we show that intracellular IL-1␣ fused to the Gal4p DNA-binding domain (Gal4BD) possesses strong transactivation potential that can be boosted by overexpression of the transcriptional coactivator p300. We demonstrate that the IL-1␣ precursor interacts via its N-terminal peptide (IL-1NTP) with histone acetyltransferases p300, PCAF, Gcn5 and with the adaptor component Ada3, and that it integrates into the PCAF⅐p300 complex in a non-destructive manner. In analogy with known acidic coactivators, yeast strains expressing Gal4BD/IL-1NTP display a toxic phenotype that can be relieved by depletion of various components of the SAGA complex. Our data provide the first solid evidence for the nuclear target of the IL-1␣ precursor and suggest its novel function in transcriptional control.

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“…Finally, physical interaction of HAX-1 with the 3Ј untranslated region of human vimentin mRNA (24) indicates RNA-binding capacity and, as interaction factor of the IL-1␣ N terminus (25), HAX-1 seems to act as cytoplasmic retention factor.…”

Section: Hs1-associated Protein X-1 Interacts With Membrane-boundmentioning

confidence: 99%

HS1-Associated Protein X-1 Interacts with Membrane-Bound IgE: Impact on Receptor-Mediated Internalization

Oberndorfer

Schmid

Geisberger

et al. 2006

The Journal of Immunology

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Engagement of the BCR triggers signals that control affinity maturation, memory induction, differentiation, and various other physiological processes in B cells. In previous work, we showed that truncation of the cytoplasmic tail of membrane-bound Ig (mIg)E in vivo resulted in lower serum IgE levels, decreased numbers of IgE-secreting plasma cells, and the abrogation of specific secondary responses correlating with a defect in the selection of high-affinity Abs during the germinal center reaction. We concluded that the Ag receptor is necessary at all times during Ab responses not only for the maturation process, but also for the expansion of Ag-specific B cells. Based on these results, we asked whether the cytoplasmic tail of mIgE, or specific proteins binding the cytoplasmic tail in vivo commit a signal transduction accompanying the B cell along its differentiation process. In this study, we present the identification of HS1-associated protein X-1 as a novel protein interacting with the cytoplasmic tail of mIgE. ELISA, surface plasmon resonance analysis, and coimmunoprecipitation experiments confirmed the specific interaction in vitro. In functional assays, we clearly showed that HS1-associated protein X-1 expression levels influence the efficiency of BCR-mediated Ag internalization.

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EVIDENCE THAT HAX-1 IS AN INTERLEUKIN-1α N-Terminal BINDING PROTEIN

Cited by 38 publications

References 80 publications

The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Intracellular Interleukin-1α Functionally Interacts with Histone Acetyltransferase Complexes

HS1-Associated Protein X-1 Interacts with Membrane-Bound IgE: Impact on Receptor-Mediated Internalization

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