The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

Abstract

<jats:p>Protein folding is a complex, error-prone process that often results in an irreparable protein by-product. These by-products can be recognized by cellular quality control machineries and targeted for proteasome-dependent degradation. The folding of proteins in the secretory pathway adds another layer to the protein folding “problem,” as the endoplasmic reticulum maintains a unique chemical environment within the cell. In fact, a growing number of diseases are attributed to defects in secretory protein folding, and many of these by-products are targeted for a process known as endoplasmic reticulum-associated degradation (ERAD). Since its discovery, research on the mechanisms underlying the ERAD pathway has provided new insights into how ERAD contributes to human health during both normal and diseases states. Links between ERAD and disease are evidenced from the loss of protein function as a result of degradation, chronic cellular stress when ERAD fails to keep up with misfolded protein production, and the ability of some pathogens to coopt the ERAD pathway. The growing number of ERAD substrates has also illuminated the differences in the machineries used to recognize and degrade a vast array of potential clients for this pathway. Despite all that is known about ERAD, many questions remain, and new paradigms will likely emerge. Clearly, the key to successful disease treatment lies within defining the molecular details of the ERAD pathway and in understanding how this conserved pathway selects and degrades an innumerable cast of substrates.</jats:p>

Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…For similar reasons, although causal evidence is still lacking, one can envisage the implication of derlins in protein folding diseases of the secretory pathway, included inflammatory bowel disease and type II diabetes [74].…”

ERAD‐dependent control of the Wnt secretory factor Evi

“…Following coordinated recognition and delivery to membrane‐embedded ubiquitination machineries, ERAD substrates are retrotranslocated across the ER membrane into the cytosol through the AAA‐ATPase VCP (also known as p97) and degraded by 26S proteasomes (Ye et al , 2001; Vembar & Brodsky, 2008; Smith et al , 2011; Olzmann et al , 2015). Since ERAD‐dependent quality control has been linked to a range of cellular processes and human diseases (Zettl et al , 2011; Guerriero & Brodsky, 2012; Perrody et al , 2016), understanding its molecular mechanisms is an important step to develop potential treatment strategies (Tsai & Weissman, 2010; Hetz et al , 2013). In addition to its role in protein quality control of nascent polypeptides, ERAD has been implicated in regulating the abundance of mature proteins in response to changes in physiological conditions (Wiertz et al , 1996a,b; Sever et al , 2003; Brodsky & Fisher, 2008; Adle et al , 2009; Foresti et al , 2013; Avci et al , 2014; van den Boomen et al , 2014).…”

Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion–Induced Acute Lung Injury

“…More evidence has suggested that ER stress is a major contributor in the development or pathology of a diseased state besides other cellular stress (15,16). The proximal "sensors" of ER stress are the chaperone grp78 (also known as BiP) along with protein kinase R-like ER kinase (PERK), activating transcription factor (ATF)6, and inositol-requiring kinase 1 (IRE1), as well as their downstream transcriptional effectors ATF4, ATF6, and X-boxbinding protein 1 (XBP1)s, respectively (17,18).…”