The cargo receptor ERGIC-53 is a target of the unfolded protein response

Nyfeler, Beat; Nufer, Oliver; Matsui, Toshie; Mori, Kazutoshi; Hauri, Hans‐Peter

doi:10.1016/s0006-291x(03)00634-x

Cited by 31 publications

(22 citation statements)

References 42 publications

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“…The evidence presented in this paper shows that both expression level and recycling pathway of the protein are modulated by heat shock. While this work was in progress, it was shown that ERGIC-53 is transcriptionally activated during UPR (24). Our results confirm this observation and, interestingly, show that the accumulation of ERGIC-53 during heat shock is driven only by enhanced translation of its mRNA.…”

supporting

confidence: 88%

Heat Shock Induces Preferential Translation of ERGIC-53 and Affects Its Recycling Pathway

Spatuzza

Renna

Faraonio

et al. 2004

Journal of Biological Chemistry

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ERGIC-53 is a lectin-like transport receptor protein, which recirculates between the ER and the Golgi complex and is required for the intracellular transport of a restricted number of glycoproteins. We show in this article that ERGIC-53 accumulates during the heat shock response. However, at variance with the unfolded protein response, which results in enhanced transcription of ERGIC-53 mRNA, heat shock leads only to enhanced translation of ERGIC-53 mRNA. In addition, the half-life of the protein does not change during heat shock. Therefore, distinct signal pathways of the cell stress response modulate the ERGIC-53 protein level. Heat shock also affects the recycling pathway of ERGIC-53. The protein rapidly redistributes in a more peripheral area of the cell, in a vesicular compartment that has a lighter sedimentation density on sucrose gradient in comparison to the compartment that contains the majority of ERGIC-53 at 37°C. This effect is specific, as no apparent reorganization of the endoplasmic reticulum, intermediate compartment and Golgi complex is morphologically detectable in the cells exposed to heat shock. Moreover, the anterograde transport of two unrelated reporter proteins is not affected. Interestingly, MCFD2, which interacts with ERGIC-53 to form a complex required for the ER-to-Golgi transport of specific proteins, is regulated similarly to ERGIC-53 in response to cell stress. These results support the view that ERGIC-53 alone, or in association with MCFD2, plays important functions during cellular response to stress conditions.

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supporting

confidence: 88%

Heat Shock Induces Preferential Translation of ERGIC-53 and Affects Its Recycling Pathway

Spatuzza

Renna

Faraonio

et al. 2004

Journal of Biological Chemistry

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“…A relationship between the ER exit and the UPR, namely through the modulation of cargo proteins' levels, has already been described, suggesting that this stress response affects protein traffic from and beyond the ER (36,37). The finding that the time spent by MHC-I complexes in the ER determines the extent of the peptide-loading optimization (38) suggests that its reduced cell surface expression in HFE C282Y mutant cells is the outcome of an incomplete peptide optimization due to the premature ER release in UPR active cells.…”

Section: Discussionmentioning

confidence: 98%

Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression

Almeida

Fleming

Azevedo

et al. 2007

The Journal of Immunology

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HFE C282Y is an example of a mutant protein that does not fold correctly, is retained in the endoplasmic reticulum, and was found previously to diminish surface expression of MHC class I (MHC-I). We now show that its expression in 293T cells triggers an unfolded protein response (UPR), as revealed by the increased levels of H chain binding protein, GRP94, and C/EBP homologous protein. Elevated levels of these proteins were also found in HFE C282Y homozygous PBMCs. Following the UPR induction, a decrease in MHC-I cell surface expression was observed. This defect in MHC-I could be mimicked, however, by overexpression of transcriptionally active isoforms of activating transcription factor-6 and X box-binding protein-1, which induced the UPR, and reversed in HFE C282Y-expressing cells by using dominant-negative constructs that block UPR signaling. The present results provide evidence to the finding that stimulation of an UPR affects MHC-I expression.

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“…Therefore, we tested whether Ca V 2.2 current suppression by Ca V ␥ 2 involved activation of the UPR. Initially, we investigated the effects of genistein, a tyrosine kinase inhibitor that prevents full expression of the UPR through inactivation of the transcription factor NF-Y (nuclear factor Y) (Zhou and Lee, 1998;Nyfeler et al, 2003). After 6 h treatment with the drug (140 M), there was no significant change in I Ba density of Ca V ␥ 2 -expressing cells (Fig.…”

Section: N-linked Protein Glycosylation Is Not a Major Determinant Formentioning

confidence: 99%

Inhibition of Recombinant N-Type Ca_VChannels by the γ₂Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms

Sandoval

Andrade²,

Beedle³

et al. 2007

J. Neurosci.

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Auxiliary ␥ subunits are an important component of high-voltage-activated calcium (Ca V ) channels, but their precise regulatory role remains to be determined. In the current report, we have used complementary approaches including molecular biology and electrophysiology to investigate the influence of the ␥ subunits on neuronal Ca V channel activity and expression. We found that coexpression of ␥ 2 or ␥ 3 subunits drastically inhibited macroscopic currents through recombinant N-type channels (Ca V 2.2/␤ 3 /␣ 2 ␦) in HEK-293 cells. Using inhibitors of internalization, we found that removal of functional channels from the plasma membrane is an improbable mechanism of current regulation by ␥. Instead, changes in current amplitude could be attributed to two distinct mechanisms. First, ␥ subunit expression altered the voltage dependence of channel activity. Second, ␥ subunit expression reduced N-type channel synthesis via activation of the endoplasmic reticulum unfolded protein response. Together, our findings (1) corroborate that neuronal ␥ subunits significantly downregulate Ca V 2.2 channel activity, (2) uncover a role for the ␥ 2 subunit in Ca V 2.2 channel expression through early components of the biosynthetic pathway, and (3) suggest that, under certain conditions, channel protein misfolding could be induced by interactions with the ␥ subunits, supporting the notion that Ca V channels constitute a class of difficult-to-fold proteins.

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The cargo receptor ERGIC-53 is a target of the unfolded protein response

Cited by 31 publications

References 42 publications

Heat Shock Induces Preferential Translation of ERGIC-53 and Affects Its Recycling Pathway

Heat Shock Induces Preferential Translation of ERGIC-53 and Affects Its Recycling Pathway

Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression

Inhibition of Recombinant N-Type Ca_VChannels by the γ₂Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms

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The cargo receptor ERGIC-53 is a target of the unfolded protein response

Cited by 31 publications

References 42 publications

Heat Shock Induces Preferential Translation of ERGIC-53 and Affects Its Recycling Pathway

Heat Shock Induces Preferential Translation of ERGIC-53 and Affects Its Recycling Pathway

Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression

Inhibition of Recombinant N-Type CaVChannels by the γ2Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms

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Inhibition of Recombinant N-Type Ca_VChannels by the γ₂Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms