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.

Anticancer chemotherapeutics often rely on induction of apoptosis in rapidly dividing cells. While these treatment strategies are generally effective in debulking the primary tumor, post-therapeutic recurrence and metastasis are pervasive concerns with potentially devastating consequences. We demonstrate that the amiloride derivative 5-(N,N-hexamethylene) amiloride (HMA) harbors cytotoxic properties particularly attractive for a novel class of therapeutic agent. HMA is potently and specifically cytotoxic toward breast cancer cells, with remarkable selectivity for transformed cells relative to non-transformed or primary cells. Nonetheless, HMA is similarly cytotoxic to breast cancer cells irrespective of their molecular profile, proliferative status, or species of origin, suggesting that it engages a cell death mechanism common to all breast tumor subtypes. We observed that HMA induces a novel form of caspase- and autophagy-independent programmed necrosis relying on the orchestration of mitochondrial and lysosomal pro-death mechanisms, where its cytotoxicity was attenuated with ROS-scavengers or lysosomal cathepsin inhibition. Overall, our findings suggest HMA may efficiently target the heterogeneous populations of cancer cells known to reside within a single breast tumor by induction of a ROS- and lysosome-mediated form of programmed necrosis.