Visiting the ER: The endoplasmic reticulum as a target for therapeutics in traffic related diseases☆

Deficiency of Suppressor Enhancer Lin12 1 Like (SEL1L) in Mice Leads to Systemic Endoplasmic Reticulum Stress and Embryonic Lethality

“…Several cellular conditions, such as high demand for protein synthesis and secretion (3,4), viral infection (5), deprivation of nutrients/oxygen (6,7), and missense mutations affecting both client protein folding (8 -11) and ER folding machinery function (2) enhance protein misfolding and cause accumulation of unfolded or misfolded proteins, leading to ER stress. Mammalian cells use several adaptive mechanisms, collectively known as the unfolded protein response (UPR), to cope with acute ER stress (12). Upon ER stress, translation is generally attenuated to reduce production of ER client proteins.…”

Lost after translation

“…On a déjà dénombré plus de 60 maladies dues à une mutation affectant le trafic post-traductionnel [19,23,24]. Parmi elles figure notamment la mutation deltaF508 dans le gène CFTR qui affecte 2/3 des malades atteints de mucoviscidose [25].…”

“…De plus, en provoquant un relâ-chement de la vigilance du système ERAD on court le risque théorique de laisser échapper non seulement l'allèle désiré mais d'autres espèces malformées dont l'effet pourrait être néfaste. Dans cet ordre d'idée on cherche activement des molécules diffusibles agissant uniquement sur l'allèle pathologique, d'où l'appellation de « chaperon pharmacologique » [24,27]. Cette spé-cificité a été obtenue, paradoxalement, avec des inhibiteurs compétitifs qui, à faibles doses, se lient à la cible par une liaison de type enzyme-substrat et l'aident à atteindre la configuration normale [28].…”

N-Glycan-dependent and -independent Quality Control of Human δ Opioid Receptor N-terminal Variants

“…4 A majority of these proteins are co-translationally glycosylated with N-glycans that are added to asparagine residues in the Asn-Xaa-(Ser/Thr) (where Xaa Pro) sequons (1,2). The N-glycans increase solubility and prevent aggregation of nascent glycoproteins and furthermore mediate interactions with lectin molecular chaperones and other factors in the ER.…”

“…The importance of ER surveillance mechanisms is demonstrated by the various diseases associated with proteins that fail to pass the QC checkpoints (4). For example, mutant forms of a number of polytopic membrane proteins, such as G proteincoupled receptors (GPCRs) rhodopsin and V2 vasopressin and melanocortin-4 receptors, are characterized by ER retention, which is one of the underlying causes for retinitis pigmentosa, nephrogenic diabetes insipidus, and morbid obesity, respectively (5-7).…”