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Membrane Protein Quantity Control at the Endoplasmic Reticulum

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Abstract

The canonical function of the endoplasmic reticulum-associated degradation (ERAD) system is to enforce quality control among membrane-associated proteins by targeting misfolded secreted, intra-organellar, and intramembrane proteins for degradation. However, increasing evidence suggests that ERAD additionally functions in maintaining appropriate levels of a subset of membrane-associated proteins. In this ‘quantity control’ capacity, ERAD responds to environmental cues to regulate the proteasomal degradation of specific ERAD substrates according to cellular need. In this review, we discuss in detail seven proteins that are targeted by the ERAD quantity control system. Not surprisingly, ERAD-mediated protein degradation is a key regulatory feature of a variety of ER-resident proteins, including HMG-CoA reductase, cytochrome P450 3A4, IP3 receptor, and type II iodothyronine deiodinase. In addition, the ERAD quantity control system plays roles in maintaining the proper stoichiometry of multi-protein complexes by mediating the degradation of components that are produced in excess of the limiting subunit. Perhaps somewhat unexpectedly, recent evidence suggests that the ERAD quantity control system also contributes to the regulation of plasma membrane-localized signaling receptors, including the ErbB3 receptor tyrosine kinase and the GABA neurotransmitter receptors. For these substrates, a proportion of the newly synthesized yet properly folded receptors are diverted for degradation at the ER, and are unable to traffic to the plasma membrane. Given that receptor abundance or concentration within the plasma membrane plays key roles in determining signaling efficiency, these observations may point to a novel mechanism for modulating receptor-mediated cellular signaling.

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Acknowledgments

Salary support for the authors was provided by NIH predoctoral fellowship CA165546 (IP), and by NIH Grants CA123541, CA166412 and CA178681 (KLC).

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  1. Department of Biochemistry and Molecular Medicine, and UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Research Building III, Room 1100B, 4645 2nd Avenue, Sacramento, CA, 95817, USA

    Ignat Printsev, Daniel Curiel & Kermit L. Carraway III

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  1. Ignat Printsev
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Printsev, I., Curiel, D. & Carraway, K.L. Membrane Protein Quantity Control at the Endoplasmic Reticulum. J Membrane Biol 250, 379–392 (2017). https://doi.org/10.1007/s00232-016-9931-0

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