Identification of Residues That Underpin Interactions within the Eukaryotic Initiation Factor (eIF2) 2B Complex

Wang, Xuemin; Wortham, Noel C.; Li, Rui; Proud, Christopher G.

doi:10.1074/jbc.m111.331553

Cited by 30 publications

(36 citation statements)

References 39 publications

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“…Plasmids encoding N‐terminal myc‐tagged eIF2B subunits and His 6 /Myc‐tagged eIF2Bε and eIF2B δ are described elsewhere (9, 15). His 6 /myc‐tagged eIF2Bα was produced by cloning the coding ORF of eIF2Bα into the pHM backbone.…”

Section: Methodsmentioning

confidence: 99%

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Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation

Wortham

Martinez

Gordiyenko³

et al. 2014

FASEB j.

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118

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Eukaryotic initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor for eIF2 and a critical regulator of protein synthesis, (e.g., as part of the integrated stress response). Certain mutations in the EIF2B genes cause leukoencephalopathy with vanishing white matter (VWM), an often serious neurological disorder. Comprising 5 subunits, α-ε (eIF2Bε being the catalytic one), eIF2B has always been considered an αβγδε heteropentamer. We have analyzed the subunit interactions within mammalian eIF2B by using a combination of mass spectrometry and in vivo studies of overexpressed complexes to gain further insight into the subunit arrangement of the complex. Our data reveal that eIF2B is actually decameric, a dimer of eIF2B(βγδε) tetramers stabilized by 2 copies of eIF2Bα. We also demonstrate a pivotal role for eIF2Bδ in the formation of eIF2B(βγδε) tetramers. eIF2B(αβγδε)2 decamers show greater binding to eIF2 than to eIF2B(βγδε) tetramers, which may underlie the increased activity of the former. We examined the levels of eIF2B subunits in a panel of different mouse tissues and identified different levels of eIF2B subunits, particularly eIF2Bα, which implies heterogeneity in the cellular proportions of eIF2B(αβγδε) and eIF2B(βγδε) complexes, with important implications for the regulation of translation in individual cell types.

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Section: Methodsmentioning

confidence: 99%

“…The N‐terminal part of eIF2Bε shows sequence similarity to eIF2Bγ (7, 8). We recently showed that highly conserved residues within the regions of human eIF2Bγ and ‐ε are crucial for their mutual interaction (9). eIF2Bα, β, and δ also show mutual sequence similarity (10); in yeast, they form a stable heterotrimeric subcomplex (11).…”

mentioning

confidence: 99%

Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation

Wortham

Martinez

Gordiyenko³

et al. 2014

FASEB j.

Self Cite

118

View full text Add to dashboard Cite

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“…These molecules have been termed alarmins or danger-associated molecular patterns, and include High Mobility Group Box 1 (HMGB1), uric acid, ATP, heat shock proteins, DNA, IL-1α, and filamentous actin (Rock et al, 2010; Ahrens et al, 2012; Zhang et al, 2012). Several recent studies have suggested that uric acid, DNA, ATP, and HSP70 are involved in the immunostimulation by aluminum adjuvants (Kool et al, 2008b; Marichal et al, 2011; Riteau et al, 2012; Wang et al, 2012). Intraperitoneal injection of aluminum-containing adjuvant induced an increase of uric acid, and treatment of mice with uricase decreased activation of antigen-specific T cells in the draining lymph node suggesting a role for uric acid in the activation of the immune response by aluminum-containing adjuvants (Kool et al, 2008b).…”

Section: Aluminum Adjuvants and Dendritic Cellsmentioning

confidence: 99%

“…Injection of IRF3-deficient mice with aluminum adjuvant induced similar accumulation of inflammatory cells in the peritoneal cavity and OVA-specific IgG1 as wild-type mice, but IRF3-deficiency abolished the OVA-specific IgE response (Marichal et al, 2011), suggesting a dissociation of the IgG1 and IgE response. Subcutaneous injection of aluminum-adjuvanted-OVA induced increased expression of membrane HSP70 in splenic dendritic cells (Wang et al, 2012). A similar effect was seen upon administration of OVA with known stress-inducing compounds.…”

Section: Aluminum Adjuvants and Dendritic Cellsmentioning

confidence: 99%

Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

HogenEsch¹

2013

Front. Immun.

309

281

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Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA, and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines.

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“…Furthermore, by inactivating CHIP via deubiquitination, ataxin-3 tightly regulate the activity of CHIP within the protein quality control pathway, ensuring that it can only ubiquitinate misfolded proteins targeted for degradation. However, if CHIP is unable to remove these proteins, resulting in an accumulation of misfolded proteins, ataxin-3 again utilizes its editing activity to help sequester these proteins into structures termed aggresomes, thereby mitigating the effects of misfolded protein toxicity within the cell (Ouyang et al, 2012; Wang et al, 2012). In this pathway, ataxin-3 edits Ub conjugates on misfolded proteins to generate free Ub C termini that are recognized by HDAC6 and subsequently sequestrated to the aggresomes (Ouyang et al, 2012).…”

Section: Ataxin-3 and Chipmentioning

confidence: 99%

Ataxin-3 and Its E3 Partners: Implications for Machado–Joseph Disease

Durcan

Fon

2013

Front. Neurol.

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Machado–Joseph disease (MJD) is the most common dominant inherited ataxia worldwide, caused by an unstable CAG trinucleotide expansion mutation within the SCA3 gene resulting in an expanded polyglutamine tract within the ataxin-3 protein. Ataxin-3 functions as a deubiquitinating enzyme (DUB), within the Ub system and whilst many DUBs are known to partner with and deubiquitinate specific E3-Ub ligases, ataxin-3 had no identified E3 partner until recent studies implicated parkin and CHIP, two neuroprotective E3 ligases. MJD often presents with symptoms of Parkinson disease (PD), which led to identification of parkin as a novel E3-Ub ligase whose activity was regulated by ataxin-3-mediated deubiquitination. Findings from these studies also revealed an unexpected convergence upon the E2-Ub-conjugating enzyme in the regulation of an E3/DUBenzyme pair. Moreover, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of the Parkinsonian features in MJD. In addition to parkin, the U-box E3 ligase CHIP, a neuroprotective E3 implicated in protein quality control, was identified as a second E3 partner of ataxin-3, with ataxin-3 regulating the ability of CHIP to ubiquitinate itself. Indeed, ataxin-3 not only deubiquitinated CHIP, but also trimmed Ub conjugates on CHIP substrates, thereby regulating the length of Ub chains. Interestingly, when expanded ataxin-3 was present, CHIP levels were also reduced in the brains of MJD transgenic mice, raising the possibility that loss of one or both E3 partners may be a contributing factor in the pathogenesis of SCA3. In this review we discuss the implications from these studies and describe the importance of these findings in helping us understand the molecular processes involved in SCA3 and other neurodegenerative disorders.

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Identification of Residues That Underpin Interactions within the Eukaryotic Initiation Factor (eIF2) 2B Complex

Cited by 30 publications

References 39 publications

Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation

Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation

Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

Ataxin-3 and Its E3 Partners: Implications for Machado–Joseph Disease

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