Expression of IFNγR2 mutated in a dileucine internalization motif reinstates IFNγ signaling and apoptosis in human T lymphocytes

Boselli, Daniela; Ragimbeau, Josiane; Orlando, Luciana; Cappello, Paola; Capello, Michela; Ambrogio, Chiara; Chiarle, Roberto; Marsili, Giulia; Battistini, Angela; Giovarelli, Mirella; Pellegrini, Sandra; Novelli, Francesco

doi:10.1016/j.imlet.2010.08.005

Cited by 12 publications

(6 citation statements)

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“…As the genes encoding the receptors for IFNα1 and 2, and for IFN-γ (IFNAR1, IFNAR2, and IFNGR2) are located on chromosome 21 [106,107] and are therefore all subject to triplication in trisomy 21. IFNAR1 and IFNAR2 respond to IFNα, β, or γ and, upon ligand binding, activate the signaling pathway for induction of proinflammatory cytokines, including IL-1β, TNFα, and IL-6 expression [127].…”

Section: Introductionmentioning

confidence: 99%

Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

Wilcock

Griffin

2013

J Neuroinflammation

186

175

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Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer’s disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the β-amyloid (Aβ) present in the Aβ plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product - the pluripotent immune cytokine interleukin-1 (IL-1) - and a chromosome 21 gene product - S100B - in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

Wilcock

Griffin

2013

J Neuroinflammation

186

175

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“…Therefore, the nanoscale organization of the activated IFN-R at the plasma membrane allows a clear dichotomy between IFN-α and IFN-γ for JAK/STAT signaling (Figure 2). In T lymphocytes, the mutation of the IFNGR2 LI endocytic motif led to cell surface accumulation and increased STAT1 activation further demonstrating the role of IFNGR localization at the plasma membrane for the activation of JAK/STAT signaling (15). …”

Section: Endocytosis and Signalingmentioning

confidence: 99%

“…Likewise, an YRGL motif is present on position 273–276 and a LI doublet is found on position 255–256 of IFNGR2 (14). The deletion of these motifs impairs the internalization of IFN-γ and the uptake of IFNGR2 and IFNGR1 subunits (15–18). The deletion of the corresponding LI motif on IFNGR2 does not result in a strong inhibition of its endocytosis, implying that the tyrosine-based endocytic motifs are also required for efficient uptake (15).…”

Section: The Classical Clathrin and Dynamin Dependent Endocytosismentioning

confidence: 99%

“…The deletion of these motifs impairs the internalization of IFN-γ and the uptake of IFNGR2 and IFNGR1 subunits (15–18). The deletion of the corresponding LI motif on IFNGR2 does not result in a strong inhibition of its endocytosis, implying that the tyrosine-based endocytic motifs are also required for efficient uptake (15). Accordingly, it was shown in 2006 that RNAi-mediated silencing of clathrin and dynamin led to the accumulation of IFNGR1 at the plasma membrane and inhibition of IFN-γ endocytosis in several cell types (19).…”

Section: The Classical Clathrin and Dynamin Dependent Endocytosismentioning

confidence: 99%

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Interferon Gamma Receptor: The Beginning of the Journey

Blouin¹,

Lamaze²

2013

Front. Immunol.

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Our view of endocytosis and membrane trafficking of transmembrane receptors has dramatically changed over the last 20 years. Several new endocytic routes have been discovered and mechanistically characterized in mammalian cells. Long considered as a passive means to terminate signaling through down-regulation of the number of activated receptors at the plasma membrane, it is now established that receptor endocytosis and endosomal sorting can be directly linked to the regulation of intracellular signaling pathways. The functional links between membrane trafficking of interferon receptors and JAK/STAT signaling have recently begun to be unraveled. These studies raise the exciting possibility that a certain level of signal specificity can be achieved through endocytosis and selective localization of the activated complexes within cellular membranes. The ongoing development of high-resolution cell imaging techniques with better spatial and temporal resolution gives new means of deciphering the inherent complexity of membrane trafficking and signaling. This should help to better comprehend the molecular mechanisms by which endocytosis and endosomal sorting of interferon receptors can orchestrate signaling selectivity within the JAK/STAT pathway that can be activated by as many as 60 different cytokines, growth factors, and hormones.

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“…In support of this assumption, deletions of the intracellular domain of IFN-␥R1, caused by common mutations, lead to overaccumulation of truncated receptors on the cell surface [9]. For IFN-␥R2, a member of the same class II cytokine receptor family as IFN-␥R1 and its partner in IFN-␥ signaling, the dileucine motif LI255-256 was identified as the receptor internalization consensus region [10,11]. Interestingly, the sequence surrounding IFN-␥R2 LI255-256 showed characteristics of tyrosine-based and dileucine-based endocytosis motifs: 252YR-GLI256, where YRGL corresponds to the tyrosine-based endocytosis motif (YxxØ) and blends into the dileucine-based endocytosis motif LI255-256.…”

Section: Introductionmentioning

confidence: 96%

A novel internalization motif regulates human IFN-γR1 endocytosis

Yancoski

Sadat

Aksentijevich

et al. 2012

Journal of Leukocyte Biology

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This study tested the hypothesis that the IFN-γ R1 287-YVSLI-91 intracellular motif regulates its endocytosis. IFN-γ exerts its biological activities by interacting with a specific cell-surface RC composed of two IFN-γ R1 and two IFN-γ R2 chains. Following IFN-γ binding and along with the initiation of signal transduction, the ligand and IFN-γ R1 are internalized. Two major types of consensus-sorting signals are described in receptors, which are rapidly internalized from the plasma membrane to intracellular compartments: tyrosine-based and dileucine-based internalization motifs. Transfection of HEK 293 cells and IFN-γ R1-deficient fibroblasts with WT and site-directed, mutagenesis-generated mutant IFN-γ R1 expression vectors helped us to identify region IFN-γ R1 287-YVSLI-291 as the critical domain required for IFN-γ-induced IFN-γ R1 internalization and Y287 and LI290-291 as part of a common structure essential for receptor endocytosis and function. This new endocytosis motif, YxxLI, shares characteristics of tyrosine-based and dileucine-based internalization motifs and is highly conserved in IFN-γ Rs across species. The IFN-γ R1 270-LI-271 dileucine motif, previously thought to be involved in this receptor endocytosis, showed to be unnecessary for receptor endocytosis.

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Expression of IFNγR2 mutated in a dileucine internalization motif reinstates IFNγ signaling and apoptosis in human T lymphocytes

Cited by 12 publications

References 44 publications

Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis

Interferon Gamma Receptor: The Beginning of the Journey

A novel internalization motif regulates human IFN-γR1 endocytosis

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