Dataset Information

Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter.

ABSTRACT: Cadmium is a highly toxic environmental contaminant that has been implicated in various disorders. A major mechanism for cadmium detoxification in the yeast Saccharomyces cerevisiae relies on extrusion via Pca1, a P-type ATPase. While an N-terminal degron targets Pca1 for degradation before its secretion to the plasma membrane, cadmium in the growth media rapidly up-regulates Pca1 by preventing its turnover. Here we show that the endoplasmic reticulum-associated degradation (ERAD) system, known for its role in quality control of secretory proteins, is unexpectedly responsible for the regulation of Pca1 expression by cadmium. Direct cadmium sensing at the ER by a degron in Pca1 leads to an escape of Pca1 from ERAD. This regulated conversion of an ERAD substrate to a secretory competent state in response to a cellular need illustrates a mechanism for expressional control of a plasma membrane protein. Yeast has likely evolved this mode of regulation for a rapid response against cadmium toxicity at the expense of constant synthesis and degradation of Pca1. ERAD of a portion of secretory proteins might occur via signal-dependent regulatory mechanisms as demonstrated for Pca1.

SUBMITTER: Adle DJ

PROVIDER: S-EPMC2700902 | biostudies-other | 2009 Jun

REPOSITORIES: biostudies-other

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Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter.

Adle David J DJ Wei Wenzhong W Smith Nathan N Bies Joshua J JJ Lee Jaekwon J

Proceedings of the National Academy of Sciences of the United States of America 20090610 25

Cadmium is a highly toxic environmental contaminant that has been implicated in various disorders. A major mechanism for cadmium detoxification in the yeast Saccharomyces cerevisiae relies on extrusion via Pca1, a P-type ATPase. While an N-terminal degron targets Pca1 for degradation before its secretion to the plasma membrane, cadmium in the growth media rapidly up-regulates Pca1 by preventing its turnover. Here we show that the endoplasmic reticulum-associated degradation (ERAD) system, known ...[more]

PMID: 19515821

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Project description:Abnormalities in posttranslational protein modifications (PTMs) that regulate protein targeting, trafficking, synthesis, and function have been implicated in the pathophysiology of schizophrenia. The endoplasmic reticulum (ER) contains specialized machinery that facilitate protein synthesis, ER entry and exit, quality control, and post-translational processing, steps required for protein maturation. Dysregulation of these systems could represent potential mechanisms for abnormalities of neurotransmitter associated proteins in schizophrenia. We hypothesized that expression of ER processing pathways is dysregulated in schizophrenia. We characterized protein and complex expression of essential components from protein folding, ER quality control (ERQC), and ER associated degradation (ERAD) processes in the dorsolateral prefrontal cortex of 12 matched pairs of elderly schizophrenia and comparison subjects. We found increased expression of proteins associated with recognizing and modifying misfolded proteins, including UDP-glucose/glycoprotein glucosyltransferase 2 (UGGT2), ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2), and synoviolin (SYVN1)/HRD1. As SYVN1/HRD1 is a component of the ubiquitin ligase HRD1-SEL1L complex that facilitates ERAD, we immunoprecipitated SEL1L and measured expression of other proteins in this complex. In schizophrenia, SYVN1/HRD1 and OS-9, ERAD promoters, have increased association with SEL1L, while XTP3-B, which can prevent ERAD of substrates, has decreased association. Abnormal expression of proteins associated with ERQC and ERAD suggests dysregulation in ER localized protein processing pathways in schizophrenia. Interestingly, the deficits we found are not in the protein processing machinery itself, but in proteins that recognize and target incompletely or misfolded proteins. These changes may reflect potential mechanisms of abnormal neurotransmitter associated protein expression previously observed in schizophrenia.

Dataset Information

Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter.

Publications

Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter.

Similar Datasets

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