Protein Quality Control in the Endoplasmic Reticulum and Cancer

Abstract

The endoplasmic reticulum (ER) is an essential compartment of the biosynthesis, folding, assembly, and trafficking of secretory and transmembrane proteins, and consequently, eukaryotic cells possess specialized machineries to ensure that the ER enables the proteins to acquire adequate folding and maturation for maintaining protein homeostasis, a process which is termed proteostasis. However, a large variety of physiological and pathological perturbations lead to the accumulation of misfolded proteins in the ER, which is referred to as ER stress. To resolve ER stress and restore proteostasis, cells have evolutionary conserved protein quality-control machineries of the ER, consisting of the unfolded protein response (UPR) of the ER, ER-associated degradation (ERAD), and autophagy. Furthermore, protein quality-control machineries of the ER play pivotal roles in the control of differentiation, progression of cell cycle, inflammation, immunity, and aging. Therefore, severe and non-resolvable ER stress is closely associated with tumor development, aggressiveness, and response to therapies for cancer. In this review, we highlight current knowledge in the molecular understanding and physiological relevance of protein quality control of the ER and discuss new insights into how protein quality control of the ER is implicated in the pathogenesis of cancer, which could contribute to therapeutic intervention in cancer.

Keywords: ER-associated protein degradation (ERAD), autophagy; cancer; endoplasmic reticulum (ER) stress; protein quality control; proteostasis; unfolded protein response (UPR) of the ER.

Figure 1

Protein quality-control machineries of the endoplasmic reticulum (ER). Protein quality-control machineries of the ER consist of three axes: acceleration of adequate protein folding, activation of the unfolded protein response (UPR), and protein clearance via ER-associated degradation (ERAD), or autophagy. UPR is composed of three transmembrane ER-resident stress sensors, inositol-requiring protein 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA (PKR)-like ER kinase (PERK). Under unstressed conditions, the luminal domains of these UPR sensors are kept inactive via binding to a chaperone, binding immunoglobulin protein (BiP). Upon ER stress, BiP dissociates from the ER sensors, leading to the activation of UPR. The PERK/ATF4 axis induces the expression of chaperones and genes involved in autophagy, apoptosis, and redox homeostasis. The IRE1/X-box binding protein 1 (XBP1) axis facilitates the transcription of a subset of UPR genes linked to adequate folding and secretion of proteins, as well as ERAD [23,24,25,26]. Activated ATF6 induces the expression of chaperones, XBP1, and genes involved in ERAD. ERAD is also the protein quality-control machinery of the ER for removing terminally misfolded, unassembled, or tightly regulated proteins via the cytosolic ubiquitin–proteasome system (UPS). Following retrotranslocation across the ER membrane, ERAD substrates are ubiquitinated and degraded by the proteasome in the cytoplasm. Black arrow, facilitation; red line, misfolded/unfolded protein.

Figure 2

ER-associated degradation (ERAD). ERAD is the conserved protein quality-control machinery of the ER for eliminating misfolded, unassembled, or tightly regulated proteins via the cytosolic ubiquitin proteasome system (UPS). Substrate recognition. Proteins failing to acquire their adequate conformation are recognized by substrate recognition factors such as osteosarcoma 9 (OS-9) for ERAD (substrate recognition). Retrotranslocation and ubiquitination. Once the substrate is recognized, it is subject to retrotranslocation and ubiquitination. Recognition of the substrate accelerates the assembly of the retrontranslocon and the initiation of substrate polyubiquitination via the sequential enzymatic system of ubiquitin E1-activating, ubiquitin E2-conjugating, and ubiquitin E3 ligase. Proteasomal degradation. The retrotranslocated substrate is eventually guided to the proteasome, thereby leading to its degradation (proteasomal degradation). Black arrow, facilitation; red line, misfolded/unfolded protein.