Protein Aggregation in the ER: Calm behind the Storm

Abstract

As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a vital role in the synthesis, folding, and assembly of secretory and membrane proteins. To maintain its homeostasis, the ER is equipped with an elaborate network of protein folding chaperones and multiple quality control pathways whose cooperative actions safeguard the fidelity of protein biogenesis. However, due to genetic abnormalities, the error-prone nature of protein folding and assembly, and/or defects or limited capacities of the protein quality control systems, nascent proteins may become misfolded and fail to exit the ER. If not cleared efficiently, the progressive accumulation of misfolded proteins within the ER may result in the formation of toxic protein aggregates, leading to the so-called “ER storage diseases”. In this review, we first summarize our current understanding of the protein folding and quality control networks in the ER, including chaperones, unfolded protein response (UPR), ER-associated protein degradation (ERAD), and ER-selective autophagy (ER-phagy). We then survey recent research progress on a few ER storage diseases, with a focus on the role of ER quality control in the disease etiology, followed by a discussion on outstanding questions and emerging concepts in the field.

Impact of SARS-CoV-2 RBD Mutations on the Production of a Recombinant RBD Fusion Protein in Mammalian Cells

“…Aggregation of misfolded proteins in the ER is responsible for the ER-stress response UPR [ 23 , 42 , 49 ]. One of the outcomes of UPR is the induction of chaperones, meant to promote protein folding.…”

“…In addition, the observation that the intracellular level of B.1.351 RBDmfc was further increased upon overexpression of PDIA2 suggests that aggregated misfolded B.1.351 RBDmfc might be normally eliminated, possibly via the ER-associated protein degradation (ERAD) pathway, in the absence of exogenous PDIA2, in order to preserve ER integrity and homeostasis [ 23 , 44 , 49 ]. This further support the idea that the overall lower yield of B.1.351 RBDmfc vs. WT RBDmfc was not due to a defect in protein translation but rather in trafficking along the secretory pathway.…”

“…Among them, the unfolded protein response (UPR) is an ER-stress response leading notably to the upregulation of chaperones such as PDIA2 or HSPA5, to enhance protein folding. In addition, protein degradation pathways are activated, including ER-associated protein degradation (ERAD), leading to the retro-translocation of the misfolded proteins into the cytosol to target their degradation by the proteasome, and ER-phagy, leading to lysosome-mediated selective degradation of ER domains [ 23 , 37 , 42 , 44 , 49 ].…”

Cryptic binding properties of a transient folding intermediate in a PDZ tandem repeat

“…In this context, it is worth to consider that sPDZD2 undergoes secretion from the cytoplasm, 15–18,22 a phenomenon that has been commonly associated to folding defects 38,39 . Indeed, a growing number of human diseases are being associated to defects in secretory protein folding, and many of these products are targeted for a process known as endoplasmic reticulum‐associated degradation 40–42 . Furthermore, it is important to note that, despite intense research and its critical role in modulating cellular proliferation and differentiation, no physiological ligand has been directly documented for native sPDZD2.…”

“…38,39 Indeed, a growing number of human diseases are being associated to defects in secretory protein folding, and many of these products are targeted for a process known as endoplasmic reticulum-associated degradation. [40][41][42] Furthermore, it is important to note that, despite intense research and its critical role in modulating cellular proliferation and differentiation, no physiological ligand has been directly documented for native sPDZD2. On the basis of these observations, it is temptative to speculate that the transient folding intermediate exerts a cryptic activity that contributes substantially to the cellular functions of sPDZD2.…”