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Role of Tandem Mass Spectrometry in Diagnosis and Management of Inborn Errors of Metabolism
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Kannan Vaidyanathan, Sandhya Gopalakrishnan
Ong et al. used MS to study Gaucher’s disease. Specific mutations are known to produce defective lysosomal enzyme folding in the endoplasmic reticulum and lead to protein degradation and loss of function. They show that nine proteins were down-regulated and two were up-regulated. Increased levels of a protein, FKBP10 accelerated degradation of mutant glucocerebroside and decreased level led to more of the enzyme entering calnexin pathway, with a positive effect on folding. They suggest that this protein could hence be used as a therapeutic target [51].
Modulating Cytolytic Responses to Infectious Pathogens
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Rebecca Pogue Caley, Jeffrey A. Frelinger
The MHC class I heavy chain (HC) and β2-microglobulin (β2M) are cotranslationally transported into the lumen of the ER. In humans, the class I heavy chain interacts with a number of chaperone proteins, including BiP and calnexin. In humans, but not mice, calnexin appears to bind free heavy chain and not the HC/β2M heterodimer [33]. In humans, this heterodimer associates with calreticulin (Figure 1). The role of calreticulin in the assembly of mouse class I is unknown. The calreticulin/ HC/βM complex binds to TAP-associated glycoprotein (Tapasin, also known as gp48K) [34,35]. Both the calreticulin and tapasin interactions in human require β2M to be bound to the heavy chain; therefore, Tapasin and calreticulin may bind to the HC/β2M heterodimer through a different site. It is unclear whether Tapasin binds alone to the calreticulin/HC/β2M complex and then binds to the TAP dimer or whether the calreticulin/HC/β2M complex binds a Tapasin/TAP complex. Either pathway causes the HC/β2M heterodimer to be located beside the point of entry of peptide into the ER lumen [34,35].
α1-Antitrypsin deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The processing of α1 AT in the endoplasmic reticulum is aided by the transmembrane chaperone calnexin which is involved in the degradation of abnormally folded proteins [62]. Misfolded proteins are dislocated to the cytosol and degraded by the ubiquitin-proteasome system, known as endoplasmic reticulum-associated degradation (ERAD) [11]. A null variant of α1-AT, Hong Kong, is a substrate for ERAD. Wild type AT was transported to the Golgi, and its carbohydrates were modified into complex glycans. In contrast, the stay in the ER of the null protein was prolonged and had protracted interaction with calnexin. Retained incompetent glycoproteins became substrates for the α-mannosidase I that tags ERAD candidates with mannose-8-glycans, which are then subject to accelerated degradation [63].
Protein misfolding, ER stress and chaperones: an approach to develop chaperone-based therapeutics for Alzheimer’s disease
Published in International Journal of Neuroscience, 2023
Rimaljot Singh, Navpreet Kaur, Neelima Dhingra, Tanzeer Kaur
ER serves as a primary site for the synthesis of secretory and integral membrane proteins[33] along with a couple of cytosolic proteins [34]. The proper functioning of proteins depends on the post-translational modifications, folding, and assembly of newly synthesized proteins. While translation continues in ER, the emerging proteins are translocated into the ER lumen via a proteinaceous pore called the translocon [35]. Once the proteins are translocated, the nascent proteins start to acquire secondary, tertiary, or quaternary structures along with several post-translational modifications including the addition of glycans, disulfide bond formation, oligomerization, proteolytic cleavage, or other processes. Most of these events are initiated inside the ER with the aid of ER-resident folding enzymes and chaperones, among them certain chaperones are calcium-dependent such as calreticulin, calnexin, GRP78, and GRP94) [36–38]. Regulation of Ca2+ ions concentration is essential for the efficient working of various molecular pathways of the cell. GRP94 is extensively responsible for the maintenance of cellular Ca2+ homeostasis [38]. Additionally, these chaperones are responsible for carrying out numerous functions including retaining proteins in a folding-competent state, catalyzing isomerization reactions, preventing secretory pathways to transport luminal protein, and regulating the degradation of misfolded proteins via a process called ERAD (ER-associated degradation) mechanism [39].
Lactiplantibacillus plantarum 299v supplementation modulates β-cell ER stress and antioxidative defense pathways and prevents type 1 diabetes in gluten-free BioBreeding rats
Published in Gut Microbes, 2022
Pinar Sargin, Mark F. Roethle, Shuang Jia, Tarun Pant, Ashley E. Ciecko, Samantha N. Atkinson, Nita H. Salzman, Ru-Jeng Teng, Yi-Guang Chen, Susanne M. Cabrera, Martin J. Hessner
All three arms of the UPR can activate ERAD, which targets misfolded proteins within the ER for ubiquitination and proteasomal degradation (Figure 3a). Independent of diet, Lp299v supplement increased UDP-glucose-glycoprotein glucosyltransferase (Uggt1) expression, which reglucosylates incompletely folded glycoproteins and promotes their reassociation with the chaperones calreticulin and calnexin. Transcripts encoding these chaperones (Calr, Canx) were also increased by HCD and Lp299v in DRlyp/lyp islets. Misfolded proteins are removed from calnexin and calreticulin by ER degradation-enhancing α-mannosidase-like protein family members (EDEM) and ER mannosidase I, fostering their retrotranslocation from the ER to the cytosol. Numerous ERAD-related transcripts (Aup1, Edem1, Edem2, Fbxo32, Man1b1, Os9, Sel1l, and Uba1) exhibited the highest expression in DRlyp/lyp HCD+Lp299v islets. Further, Serp1, which is induced by ER stress and protects unfolded proteins from ERAD, exhibited the lowest expression in DRlyp/lyp HCD+Lp299v islets. Ufd1 transcript was lowest in DRlyp/lyp HCD+Lp299v islets, repression of this ubiquitin-recognition protein triggers cell cycle delay to foster efficient ERAD-mediated clearance of misfolded protein.51 Overall, the DRlyp/lyp HCD+Lp299v islet transcriptome was consistent with enhanced ERAD activity (Figure 3b).
Murine models of dengue virus infection for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Alana B. Byrne, Cybele C. García, Elsa B. Damonte, Laura B. Talarico
Flaviviruses depend on endoplasmic reticulum (ER)-resident α-glucosidases I and II for the trimming of N-linked oligosaccharides from their three N-glycosylated proteins: prM, E, and NS1 [95]. Based on the viral dependency on this cellular enzyme activity, it is proposed that the use of sugar analogs is a promising strategy for effective anti-flaviviral therapeutics. The mimetic compounds named iminosugars, in which cyclic oxygen is replaced with nitrogen, compete with endogenous substrates for binding to ER α-glucosidases thus impairing the aforementioned terminal glucose residue removal from the viral protein. A lack of modification of the high-mannose sugars on viral proteins affects the interactions with the chaperones calnexin and calreticulin impairing the proper folding and activation of the viral proteins [96,97]. To note, patients deficient in α-glucosidases I or II showed no clinical evidence of recurrent viral infections, and cells derived from these patients were unable to support infection by multiple viruses [98,99].