Endoplasmic Reticulum-Associated Degradation (ERAD)

Abstract

The newly synthesized proteins are kept in the endoplasmic reticulum (ER) until their maturation is completed. The accurate protein folding is vital for homeostasis, but this process is error-prone since it is chemically complicated. Aberrant folding may result in aggregates having a toxic gain of function or may lead to a loss of protein function; therefore, protein misfolding can lead to several pathologies. The ER protein quality control mechanism monitors the fidelity of protein folding. Those proteins that fail to fold or assemble properly are subjected to degradation via a process known as ER-associated degradation (ERAD). Besides clearing proteins having folding problems, ERAD is also known to regulate the levels of some physiological proteins including 3-hydroxy-3-methylglutaryl- coenzymeA reductase (HMGR) catalyzing the rate-limiting step of cholesterol bio- synthesis. ERAD is a complex, multistep process starting with the recognition and targeting of substrates, followed by ubiquitination, retrotranslocation and proteasomal degradation. A large number of ERAD factors functioning in different molecular machineries increases the complexity of mammalian ERAD. ERAD is fundamental for human health and there is increasing evidence linking ERAD with various diseases. Here, the different modules/machineries of the ERAD process together with its tight regulation will be discussed.