Competing Functions Encoded in the Allergy-Associated FcϵRIβ Gene

Donnadieu, Emmanuel; Jouvin, Marie-Hélène; Rana, Shalini; Moffatt, Miriam F.; Mockford, E. H.; Cookson, William; Kinét, Jean-Pierre

doi:10.1016/s1074-7613(03)00115-8

Cited by 65 publications

(79 citation statements)

References 64 publications

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“…One prediction from this hypothesis is that the ␣␥2 complex might exhibit a measurable accumulation in the ER. In fact several studies have now shown that the ER form of the ␣-chain is produced at significantly higher levels in cells transfected with both ␣-and ␥-chains compared with ␣-/␥-/␤-transfectants (4,66). The ␤-chain is well known to function in the amplification of Fc⑀RI surface expression, and it has been suggested that it may act as a chaperone for Fc⑀RI transport primarily because of its capacity to enhance post-translational Golgi processing of the ␣-chain (66).…”

Section: Discussionmentioning

confidence: 99%

Transport of the IgE Receptor α-Chain Is Controlled by a Multicomponent Intracellular Retention Signal

Cauvi

Tian

Loehneysen

et al. 2006

Journal of Biological Chemistry

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The human high affinity IgE receptor (Fc⑀RI) is a central component of the allergic response and is expressed as either a trimeric ␣␥2 or tetrameric ␣␤␥2 complex. It has been previously described that the cytoplasmic domain (CD) of the ␣-chain carries a dilysine motif at positions ؊3/؊7 from the C terminus that functions in intracellular retention prior to assembly with other Fc⑀RI subunits. In this report we have further explored the role of the ؊3/؊7 dilysine signal in controlling steady-state ␣-chain transport by mutational analysis and found little surface expression of a ؊3/؊7 dialanine ␣-chain mutant but significant Golgi localization. We compared the transport properties of a series of ␣-chain cytoplasmic domain truncation mutants and observed that truncation mutants lacking 23 or more C-terminal residues showed a dramatic increase in steady-state transport suggesting a role for the membrane-proximal CD sequence in ␣-chain retention. By performing alanine-scanning mutagenesis we identified a dilysine sequence (Lys The high affinity IgE receptor (Fc⑀RI) 2 is a multisubunit complex comprised of either a tetrameric ␣␤␥2 complex or an alternative trimeric ␣␥2 isoform (1, 2). Aggregation of the tetrameric receptor on mast cells and basophils occurs upon cross-linking of receptor-bound IgE with a multivalent antigen that initiates Fc⑀RI-dependent signaling, culminating in cellular degranulation and the ensuing clinical symptoms of hypersensitivity. Expression of the trimeric Fc⑀RI isoform occurs on a number of cells, including monocytes, epidermal Langerhans cells, and dendritic cells, and a role for the ␣␥2 receptor in antigen presentation has now been established (3). The Fc⑀RI ␣-chain is exclusively involved in IgE binding, whereas the associated ␥-and ␤-chains function in signaling by the presence of intracellular tyrosine activation motifs. Assembly with the ␤-chain also functions to amplify Fc⑀RI cell-surface expression relative to the ␣␥2 isoform (4, 5) and represents a fundamental mechanism for the regulation of Fc⑀RI cell-surface expression. It has long been known that binding of IgE to cell-surface Fc⑀RI leads to enhanced receptor expression (6), an effect that has now been amply demonstrated for both receptor isoforms (6 -9) and is thought to involve receptor-ligand surface stabilization and possibly increased export of ␣-chain from an intracellular pool (10, 11). Additional mechanisms that regulate Fc⑀RI expression have also been identified, including the effects of interleukin-4 in mast cells (7, 12) and transforming growth factor-␤1 in both dendritic cells (13) and mast cells (14). Because the sensitivity of the allergic response is critically linked to Fc⑀RI surface expression (15) that in turn is dependent on Fc⑀RI subunit transport characteristics (16) and assembly (17), it remains an important goal to fully elucidate the Fc⑀RI structural features that regulate these processes to thereby provide a better understanding of the molecular origins of the allergic response.The underlying factors th...

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Section: Discussionmentioning

confidence: 99%

Transport of the IgE Receptor α-Chain Is Controlled by a Multicomponent Intracellular Retention Signal

Cauvi

Tian

Loehneysen

et al. 2006

Journal of Biological Chemistry

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“…Recently, it was revealed that ␤-chain amplified degranulation and leukotriene secretion but suppressed cytokine production (12), indicating that ␤-chain regulates distinct intracellular signaling events in both positive and negative manners by the same molecule of itself. Furthermore, an alternative splice variant which encoded only an N-terminal portion of ␤-chain was found to be expressed in human mast cells (13). This truncation variant competed with full-length ␤ and prevented Fc RI surface expression by inhibiting ␣-chain maturation (13).…”

mentioning

confidence: 99%

“…Furthermore, an alternative splice variant which encoded only an N-terminal portion of ␤-chain was found to be expressed in human mast cells (13). This truncation variant competed with full-length ␤ and prevented Fc RI surface expression by inhibiting ␣-chain maturation (13). Because all of these findings indicate that ␤-chain is a fine regulator of Fc RI-mediated cell activation to precisely control the allergic reaction, elucidation of regulatory mechanisms of ␤-chain expression will make a meaningful contribution to medical intervention for allergy.…”

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confidence: 99%

Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF

Takahashi

Hayashi

Kaminogawa

et al. 2006

The Journal of Immunology

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The β-chain of the high-affinity receptor for IgE (FcεRI) plays an important role in regulating activation of FcεRI-expressing cells such as mast cells in allergic reactions. We already reported that the transcription factor myeloid zinc finger (MZF) 1 which formed a high m.w. complex including four and a half LIM-only protein (FHL)3 in the nucleus repressed human β-chain gene expression through an element in the fourth intron. We also found that GM-CSF induced expression of MZF-1 and nuclear translocation of FHL3. We screened a human cDNA library and identified NFY which was reported to bind histone deacetylases (HDACs) as a constituent of the complex. The C-subunit of NFY was demonstrated to form a ternary complex with MZF-1/FHL3 and interact with a β-chain gene region including the element in the fourth intron. HDAC1 and HDAC2 were also shown to interact with the fourth intron region of the β-chain gene. In a human mast cell line HMC-1 cultured with GM-CSF, both β-chain expression and acetylation of histones interacting with the fourth intron region of the β-chain gene were decreased. Collectively, these results indicated that HDACs, which were recruited to the β-chain gene through the element in the fourth intron by MZF-1/FHL3/NFY, repressed β-chain gene transcription by deacetylation of histones in the presence of GM-CSF. These mechanisms will be involved in not only the cell type-specific repression of β-chain gene expression in differentiating hemopoietic cells but also the repression of β-chain gene expression in the peripheral cells under specific circumstances.

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“…Signals triggered by FcRβ-associated FcεRI were found to be of a higher intensity than signals triggered by FcεRI associated with FcRγ only (Dombrowicz et al, 1998). FcRβ also enhances IgE-induced allergic responses by up-regulating the surface expression of FcεRI (Donnadieu et al, 2003). Recently, however, FcRβ was found to generate ITAM-dependent negative signals.…”

Section: Fcrβmentioning

confidence: 99%

Negative Signaling in Fc Receptor Complexes

Daëron

Lesourne

2006

Advances in Immunology

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Cell activation results from the transient displacement of an active balance between positive and negative signaling. This displacement depends in part on the engagement of cell surface receptors by extracellular ligands. Among these are Receptors for the Fc portion of immunoglobulins (FcRs). FcRs are widely expressed by cells of hematopoietic orign. When binding antibodies, FcRs provide these cells with immunoreceptors capable of triggering numerous biological responses in response to specific antigen. FcR-dependent cell activation is regulated by negative signals which are generated together with positive signals within signalosomes that form upon FcR engagement. Many molecules involved in positive signaling, including the FcRβ subunit, the src kinase lyn, the cytosolic adapter Grb2, the transmembrane adapters LAT and NTAL, are indeed also involved in negative signaling. A major player in negative regulation of FcR signaling is the inositol 5-phosphatase SHIP1. Several layers of negative regulation operate sequentially as FcRs are engaged by extracellular ligands of increasing valency. A background protein tyrosine phosphatasedependent negative regulation maintains cells in a « resting » state. SHIP1-dependent negative regulation can be detected as soon as high-affinity FcRs are occupied by antibodies in the absence of antigen. It increases when activating FcRs are engaged by multivalent ligands and, further when FcR aggregation increases, accounting for the bell-shaped dose-response curve observed in excess of ligand. Finally, F-actin skeleton-associated high-molecular weight SHIP1, recruited to phopshorylated ITIMs, concentrates in signaling complexes when activating FcRs are coengaged with inhibitory FcRs by immune complexes. Based on these data, activating and inhibitory FcRs could be used for new therapeutic approaches of immune disorders.

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Competing Functions Encoded in the Allergy-Associated FcϵRIβ Gene

Cited by 65 publications

References 64 publications

Transport of the IgE Receptor α-Chain Is Controlled by a Multicomponent Intracellular Retention Signal

Transport of the IgE Receptor α-Chain Is Controlled by a Multicomponent Intracellular Retention Signal

Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF

Negative Signaling in Fc Receptor Complexes

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