Degradation and Endoplasmic Reticulum Retention of Unassembled α- and β-Subunits of Na,K-ATPase Correlate with Interaction of BiP

Beggah, Ahmed T.; Mathews, Paul M.; Béguin, Pascal; Geering, Käthi

doi:10.1074/jbc.271.34.20895

Cited by 71 publications

(52 citation statements)

References 54 publications

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“…P␣F might have become bound to and trapped in the ER by exaggerated amounts of BiP (Figure 9), but the concentrations and/or activities of cochaperones required for release might not have risen in parallel. Consistent with our work, increasing the level of BiP slows the ERAD of mutant ribophorin in mammalian cells (deVirgilio et al, 1999) and the concept that ERAD can proceed only after BiP release is well established (Knittler et al, 1995;Beggah et al, 1996;Skowronek et al, 1998;Chillaron and Haas, 2000). It is possible that under conditions of ER stress, when the concentration of BiP rises via the UPR, ERAD efficiency may decline, but the solubility of putative ERAD substrates is maintained.…”

Section: Erad-defective Mutations In Bip/kar2psupporting

confidence: 71%

“…In accordance with these hypotheses, several lines of evidence support a role for the lumenal Hsp70, BiP, in ERAD in both mammals and yeast. First, the proteolysis of ERAD substrates coincides with the rate at which they are released from BiP in the mammalian ER (Knittler et al, 1995;Beggah et al, 1996;Skowronek et al, 1998;Chillaron and Haas, 2000), and BiP associates preferentially with exposed regions of an unfolded ERAD substrate (Schmitz et al, 1995). Second, the degradation of an ERAD substrate is slowed when yeast contain a mutant allele in the gene encoding BiP, KAR2 (kar2-113;Plemper et al, 1997), and two ERAD substrates in yeast, CPY* and p␣F, aggregate in microsomes prepared from another kar2 mutant shifted to the nonpermissive temperature (kar2-203;Nishikawa et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Dependence of Endoplasmic Reticulum-associated Degradation on the Peptide Binding Domain and Concentration of BiP

Kabani

Kelley

Morrow

et al. 2003

MBoC

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ER-associated degradation (ERAD) removes defective and mis-folded proteins from the eukaryotic secretory pathway, but mutations in the ER lumenal Hsp70, BiP/Kar2p, compromise ERAD efficiency in yeast. Because attenuation of ERAD activates the UPR, we screened for kar2 mutants in which the unfolded protein response (UPR) was induced in order to better define how BiP facilitates ERAD. Among the kar2 mutants isolated we identified the ERAD-specific kar2-1 allele (Brodsky et al. J. Biol. Chem. 274,(3453)(3454)(3455)(3456)(3457)(3458)(3459)(3460). The kar2-1 mutation resides in the peptide-binding domain of BiP and decreases BiP's affinity for a peptide substrate. Peptide-stimulated ATPase activity was also reduced, suggesting that the interdomain coupling in Kar2-1p is partially compromised. In contrast, Hsp40 cochaperone-activation of Kar2-1p's ATPase activity was unaffected. Consistent with UPR induction in kar2-1 yeast, an ERAD substrate aggregated in microsomes prepared from this strain but not from wild-type yeast. Overexpression of wild-type BiP increased substrate solubility in microsomes obtained from the mutant, but the ERAD defect was exacerbated, suggesting that simply retaining ERAD substrates in a soluble, retro-translocationcompetent conformation is insufficient to support polypeptide transit to the cytoplasm. INTRODUCTIONBefore being delivered to their ultimate locations, secreted proteins are monitored by a quality control "machine" associated with the endoplasmic reticulum (ER; reviewed by Ellgaard et al., 1999); aberrant polypeptides may be retrotranslocated from the ER to the cytoplasm and destroyed by the proteasome in a process termed ER-associated degradation (ERAD; McCracken and Brodsky, 1996). The importance of defining the molecular mechanism of ERAD is underscored by the fact that several human diseases arise from the accumulation or accelerated degradation of ERAD substrates and because some bacterial toxins and viruses coopt the ERAD pathway to exert their effects (reviewed in Thomas et al., 1995;Aridor and Hannan, 2000;Fewell et al., 2001).ERAD may result from inefficient protein folding, so it is not surprising that molecular chaperones are required for this process. Chaperones prevent the formation of off-pathway intermediates or directly catalyze folding and have been proposed to "judge" whether a nascent protein will ultimately fold or whether it should be targeted for degradation (reviewed by Hayes and Dice, 1996;Hartl, 1996;Horwich et al., 1999;Plemper and Wolf, 1999;Rö misch, 1999;Wickner et al., 1999;Fewell et al., 2001;Hö hfeld et al., 2001). Hsp70 (heat shock proteins with a molecular mass of ϳ70 kDa) molecular chaperones hydrolyze ATP concomitant with the binding of peptides with overall hydrophobic character (Flynn et al., 1991;Blond-Elguindi et al., 1993;Rü diger et al., 1997); therefore, Hsp70s might retain the solubility of unfolded, retro-translocating polypeptides during their voyage from the ER to the cytoplasm via the Sec61p translocation channel or might "gate" this c...

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Section: Erad-defective Mutations In Bip/kar2psupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Dependence of Endoplasmic Reticulum-associated Degradation on the Peptide Binding Domain and Concentration of BiP

Kabani

Kelley

Morrow

et al. 2003

MBoC

View full text Add to dashboard Cite

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“…Na, K-ATPase consists of α and β subunits. The glycosylated β subunit has been proposed to facilitate the assembly and transport of the α subunit from the endoplasmic reticulum to the plasma membrane (20,21), and the β subunit is the key factor in polarizing distribution of Na, K-ATPase (22). The results of the present study showed that the HCMV UL136 protein has the ability to interact with ATP1B1.…”

Section: Discussionsupporting

confidence: 54%

Interaction between human cytomegalovirus UL136 protein and ATP1B1 protein

Cui

Sun

Ren

et al. 2011

Braz J Med Biol Res

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“…Newly synthesized proteins are screened by ER resident proteins, immunoglobulin binding proteins (BiP). Misfolded poly-peptides and unassembled subunits of oligomeric proteins are captured by BiP, retained in the ER, and rapidly degraded in the lumen of the ER (Bonifacino et al, 1989;Klausner and Sitia, 1990;Sitia et al, 1990;Wileman et al, 1990;Wikstorm and Lodish, 1992;Beggah et al, 1996). This rapid and selective degradation of proteins have been described as preGolgi or ER degradation (Lippincoctt-Scchwartz et al , 1988).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum retention and degradation of T cell antigen receptor β chain

Lee

1998

Exp Mol Med

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The T cell antigen receptor-CD3 (TCR/CD3) complex is assembled in the endoplasmic reticulum (ER) of T cells after synthesis of individual chains, and is transported to the cell surface for immune recognition and regulation. Partially assembled or unassembled TCR chains are retained and rapidly degraded in the ER. These processes are strictly regulated in the ER at post-translational level for the maintenance of cellular homeostasis. In order to identify the region responsible for the ER retention and rapid degradation of the TCR chain, number of mutants were engineered and their fates, after synthesis in the ER of the HeLa cells, were investigated. Extensive mutagenic analysis of TCR chain, including changing the charged amino acid residues and two tyrosine residues of the transmembrane region into hydrophobic amino acid residues, did not alter the ER retention and rapid degradation. Soluble TCR chain and cytoplasmic tail truncation mutant were also rapidly degraded in the ER. However, N-glycosylation rate of soluble TCR chain in the ER was significantly increased possibily due to the increased exposure of the N-glycosylation site. These results suggest that the ER retention of TCR chain is mediated through its extracellular and transmembrane-cytoplasmic regions and that the rapid ER degradation can be caused by an exposure of unassembled subregion of TCR chain, either extracellular domain or hydrophobic transmembrane region to the hydrophilic environment (lumen of the ER) rather than by presence of a specific degradation signal.

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Degradation and Endoplasmic Reticulum Retention of Unassembled α- and β-Subunits of Na,K-ATPase Correlate with Interaction of BiP

Cited by 71 publications

References 54 publications

Dependence of Endoplasmic Reticulum-associated Degradation on the Peptide Binding Domain and Concentration of BiP

Dependence of Endoplasmic Reticulum-associated Degradation on the Peptide Binding Domain and Concentration of BiP

Interaction between human cytomegalovirus UL136 protein and ATP1B1 protein

Endoplasmic reticulum retention and degradation of T cell antigen receptor β chain

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