Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?

Abstract

<jats:p>Endoplasmic reticulum glycoprotein folding quality control (ERQC) and ER-associated degradation (ERAD) preside over cellular glycoprotein secretion and maintain steady glycoproteostasis. When cells turn malignant, cancer cell plasticity is affected and supported either by point mutations, preferential isoform selection, altered expression levels, or shifts to conformational equilibria of a secreted glycoprotein. Such changes are crucial in mediating altered extracellular signalling, metabolic behavior, and adhesion properties of cancer cells. It is therefore conceivable that interference with ERQC and/or ERAD can be used to selectively damage cancers. Indeed, inhibitors of the late stages of ERAD are already in the clinic against cancers such as multiple myeloma. Here, we review recent advances in our understanding of the complex relationship between glycoproteostasis and cancer biology and discuss the potential of ERQC and ERAD modulators for the selective targeting of cancer cell plasticity.</jats:p>

Clamping, bending, and twisting inter-domain motions in the misfold-recognising portion of UDP-glucose:glycoprotein glucosyl-transferase

“…Our observation that the UGGT TRXL2 domain surface facing the central saddle bears distinct patches of hydrophobic residues that are conserved across UGGT1 and UGGT2 sequences [5] supports such models of misfold recognition. The fact that UGGT bears de-mannosylated glycans -a hallmark of ER associated degradation (ERAD) [30,31] -is also compatible with the hypothesis that UGGT may recognise misfolded glycoproteins via an intrinsically misfolded domain ("it takes one to know one" [22]), as observed for the mouse ERAD checkpoint mannosidase, which also preferentially acts on misfolded glycoproteins and has been proven to undergo constant ERAD degradation [32].…”

“…If this is the case, the "UGGT1-ome" and "UGGT2-ome" (defined as full lists of clients of UGGT1 and UGGT2, respectively [22] [5]), with one study speculating large relative movements between the two portions of the UGGT molecule thanks to this flexible linker [6,7]. In this 'reach-and-grab' model, UGGT would preferentially bind and re-glucosylate glycans close to the site of misfold, but would also be able to extend to re-glucosylate distal glycans in neighboring folded regions, if the GT24 were to escape the embrace of the βS1-βS2 domains [13].…”

Oligosaccharyltransferase: A Gatekeeper of Health and Tumor Progression

“…However, the efficacy and target molecules in each tumor type remain to be defined if undesired side effects are to be prevented and the effects of OST blockade on possible tumor treatment is to be maximized. In this regard, the toxicity associated with the inhibition of OST should be considered carefully, as OST inhibition affects global N-glycosylation, which may generate undesired proteins, result in detrimental effects to healthy cells, and complicate cancers [97]. Thus, efforts should be made to understand the inhibitory mechanisms of NGI-1, as well as the precise functions of accessory subunits of OST in N-glycosylation and tumor progression, which will accelerate structure-based drug design and discovery.…”

Erratum to “Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?”

“…Plasticity, an intrinsic characteristic of healthy cells in biological contexts as varied as embryonal development [1], tissue development and repair [2], adaptation to injury [3], and wound healing [4], is also central to cancer initiation, progression, and metastasis. e proteins establishing and maintaining cancer plasticity are good anticancer drug targets in the fight against cancer initiation, progression, and therapy resistance itself [5].…”

“…In the article titled “Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?” [ 1 ], there was an incorrect section numbering. These errors occurred during the production process.…”