Substrate-specific mediators of ER associated degradation (ERAD)

Abstract

Approximately one-third of newly synthesized eukaryotic proteins are targeted to the secretory pathway, which is composed of an organellar network that houses the enzymes and maintains the chemical environment required for the maturation of secreted and membrane proteins. Nevertheless, this diverse group of proteins may fail to achieve their native states and are consequently selected for ER associated degradation (ERAD). Over the past few years, significant effort has been made to dissect the components of the core ERAD machinery that is responsible for the destruction of most ERAD substrates. Interestingly, however, some ERAD substrates associate with dedicated chaperone-like proteins that target them for proteolysis or protect them from destruction. Other substrates fold and function normally but can be selected for ERAD by protein adaptors that identify and transmit regulatory cues.

Fig. 1. Degradation of ERAD-L, -M, and —C substrates

Soluble and integral membrane proteins with mis-folding lesions in the lumen, and integral membrane proteins with mis-folding lesions within the membrane and in the cytoplasmic space are depicted. In nearly all cases, substrates are delivered to the proteasome for degradation in a process that requires the p97 complex (also known as the Cdc48 complex in yeast).

Fig. 2. Model of SPFH1/2 complex-mediated ERAD of activated IP₃ receptors

Upon binding of the co-agonists IP₃ and Ca²⁺, IP₃ receptor tetramers undergo a conformational change that both opens the Ca²⁺ channel to allow for the release of ER Ca²⁺ stores, and triggers association of the SPFH1/2 complex. The SPFH1/2 complex targets activated IP₃ receptors for ERAD, perhaps by recruiting the E2 and E3 that catalyze IP₃ receptor polyubiquitination. Polyubiquitinated IP₃ receptors are then extracted from the ER membrane through the action of the p97-Ufd1-Npl4 complex, and are delivered to the proteasome for degradation.