Potential Physiological Relevance of ERAD to the Biosynthesis of GPI-Anchored Proteins in Yeast.

Kunio Nakatsukasa

doi:10.3390/ijms22031061

Kunio Nakatsukasa

Open Access

https://doi.org/10.3390/ijms22031061

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Abstract

Misfolded and/or unassembled secretory and membrane proteins in the endoplasmic reticulum (ER) may be retro-translocated into the cytoplasm, where they undergo ER-associated degradation, or ERAD. The mechanisms by which misfolded proteins are recognized and degraded through this pathway have been studied extensively; however, our understanding of the physiological role of ERAD remains limited. This review describes the biosynthesis and quality control of glycosylphosphatidylinositol (GPI)-anchored proteins and briefly summarizes the relevance of ERAD to these processes. While recent studies suggest that ERAD functions as a fail-safe mechanism for the degradation of misfolded GPI-anchored proteins, several pieces of evidence suggest an intimate interaction between ERAD and the biosynthesis of GPI-anchored proteins.

Highlights

Secretory and membrane proteins are translocated to the endoplasmic reticulum (ER), where they are folded into a three-dimensional conformation
Unidentified endogenous ER-associated degradation (ERAD) substrates are key to understanding the potential relationship between ERAD and the biosynthesis of GPI-anchored proteins
The simple genetic interaction reported by systematic studies implies the existence of an endogenous ERAD substrate that may affect the phenotype of cells defective in GPI biosynthesis

Summary

Introduction

Secretory and membrane proteins are translocated to the endoplasmic reticulum (ER), where they are folded into a three-dimensional conformation. The Hrd E3 ligase complex recognizes and targets misfolded luminal proteins, as well as ER membrane proteins with lesions at the transmembrane domain, for ubiquitination and degradation (Figure 1). These pathways are the so-called ERAD-L and -M pathways, respectively [17,20,21,22,23,24,25,26,27]. Inactivation of Cdc leads to a formation of stalled retro-translocation complex containing Hrd, Usa, Hrd, Der, the 26S proteasome, Yos, ubiquitinated substrates, and Cdc. This supports the functional flexibility of the Hrd complex in response to ER stress [42,43]

The Doa10 Pathway

Quality Control of GPI-Anchored Proteins

Genetic Interactions between GPI and ERAD Genes

Conclusions