Sec61p and BiP directly facilitate polypeptide translocation into the ER

Sanders, Sylvia L.; Whitfield, Kristina M.; Vogel, Joseph P.; Rose, Mark D.; Schekman, Randy

doi:10.1016/0092-8674(92)90415-9

Cited by 367 publications

(253 citation statements)

References 60 publications

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“…We also observed accumulation of an unglycosylated form of CPY only in the type A mutant cells (unpublished data). These findings are consistent with previous reports (Vogel et al, 1990;Sanders et al, 1992) and suggest that type A and type S mutants correspond to the class I and class II kar2 mutants, respectively, defined by Brodsky and Rose (1997), based on their phenotypes. These observations strongly suggest that protein translocation into the ER is blocked only in the type A mutant strains.…”

Section: Discussionsupporting

confidence: 93%

“…Because KAR2 is essential for viability, studies of its physiological functions have been performed primarily using conditional lethal kar2 alleles. When cultured at the restrictive temperature, some of the temperature-sensitive kar2 mutant strains exhibit a block in the translocation of secretory proteins into the ER (Vogel et al, 1990;Sanders et al, 1992;Brodsky et al, 1995). Several molecular mechanisms have been proposed to explain the function of Kar2 in the protein translocation machinery (Hamman et al, 1998;Matlack et al, 1999).…”

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confidence: 99%

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Genetic Evidence for a Role of BiP/Kar2 That Regulates Ire1 in Response to Accumulation of Unfolded Proteins

Kimata

Shimizu

Abe

et al. 2003

MBoC

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In the unfolded protein response (UPR) signaling pathway, accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a transmembrane kinase/ribonuclease Ire1, which causes the transcriptional induction of ER-resident chaperones, including BiP/Kar2. It was previously hypothesized that BiP/Kar2 plays a direct role in the signaling mechanism. In this model, association of BiP/Kar2 with Ire1 represses the UPR pathway while under conditions of ER stress, BiP/Kar2 dissociation leads to activation. To test this model, we analyzed five temperaturesensitive alleles of the yeast KAR2 gene. When cells carrying a mutation in the Kar2 substratebinding domain were incubated at the restrictive temperature, association of Kar2 to Ire1 was disrupted, and the UPR pathway was activated even in the absence of extrinsic ER stress. Conversely, cells carrying a mutation in the Kar2 ATPase domain, in which Kar2 poorly dissociated from Ire1 even in the presence of tunicamycin, a potent inducer of ER stress, were unable to activate the pathway. Our findings provide strong evidence in support of BiP/Kar2-dependent Ire1 regulation model and suggest that Ire1 associates with Kar2 as a chaperone substrate. We speculate that recognition of unfolded proteins is based on their competition with Ire1 for binding with BiP/Kar2. INTRODUCTIONAccumulation of unfolded proteins in the endoplasmic reticulum (ER) results in the transcriptional induction of various genes including those encoding ER-resident chaperones and folding enzymes. This cellular mechanism is called the unfolded protein response (UPR), and several important features of the UPR signaling pathway have been revealed initially through studies in the budding yeast Saccharomyces cerevisiae. Yeast Ire1 is a 1115-amino acid transmembrane protein that transmits the unfolded protein signal across the ER membrane (Cox et al., 1993;Mori et al., 1993). The cytoplasmic domain (C-terminal half) of Ire1 possesses both serine/threonine kinase and site-specific endoribonuclease activities Sidrauski and Walter, 1997). Ire1 dimerizes in response to the accumulation of unfolded proteins, resulting in its trans-autophosphorylation and activation (Shamu and Walter, 1996;Welihinda and Kaufman, 1996). Activated Ire1 in turn promotes splicing of HAC1 precursor mRNA to produce the mature form (Cox and Walter, 1996;Sidrauski and Walter, 1997), which is effectively translated into a functional transcription factor (Mori et al., 2000;Ruegsegger et al., 2001). Mature form of Hac1 efficiently induces transcription of UPR target genes containing the UPR element (UPRE) in their promoter region (Mori et al., 1992;Kohno et al., 1993).In mammalian cells, accumulation of unfolded proteins initiates signaling from the ER via more complicated pathways. Two homologues of Ire1, Ire1␣ and Ire1␤, have been identified (Tirasophon et al., 1998;Wang et al., 1998;Iwawaki et al., 2001). According to recent reports (Yoshida et al., 2001;Calfon et al., 2002), IRE1 functions to promote splicing of an mRNA encoding ...

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Genetic Evidence for a Role of BiP/Kar2 That Regulates Ire1 in Response to Accumulation of Unfolded Proteins

Kimata

Shimizu

Abe

et al. 2003

MBoC

Self Cite

189

177

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“…Sec61p was first identified in Saccharomyces cerevisiae [10] and found to be a major cross-linking partner of secretory proteins artificially trapped during the translocation process (denoted 'translocation intermediates') [11,12]. Sec61~, the mammalian homologue of Sec61p, was isolated via its tight association with ribosomes and shown to interact with nascent secretory proteins during translocation across the ER membrane [13].…”

Section: Introductionmentioning

confidence: 99%

The Sec61 complex is essential for the insertion of proteins into the membrane of the endoplasmic reticulum

et al. 1995

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“…Like other secreted proteins, PrP bears a short endoplasmic reticulum (ER) localization signal in its N-terminus, which is first translated by the ribosome. The appearance of the signal peptide, and its recognition by the signal recognition particle (SRP) (Lauffer et al 1985), mediates an interaction between the ribosome and the ER channel protein sec61p (Sanders et al 1992). The bound ribosome cotranslationally translocates the nascent PrP molecule into the ER lumen (Fig.…”

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confidence: 99%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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Sec61p and BiP directly facilitate polypeptide translocation into the ER

Cited by 367 publications

References 60 publications

Genetic Evidence for a Role of BiP/Kar2 That Regulates Ire1 in Response to Accumulation of Unfolded Proteins

Genetic Evidence for a Role of BiP/Kar2 That Regulates Ire1 in Response to Accumulation of Unfolded Proteins

The Sec61 complex is essential for the insertion of proteins into the membrane of the endoplasmic reticulum

Protein Quality Control in Health and Disease

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