ArticleArthritis & rheumatology (Hoboken, N.J.)2014
Endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 1 targets misfolded HLA-B27 dimers for endoplasmic reticulum-associated degradation.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 37 citations in OpenAlex.
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- Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers.Frontiers in immunology · 2024Article
- Uncovering the Underworld of Axial Spondyloarthritis.International journal of molecular sciences · 2023Review
- Axial Spondyloarthritis: Reshape the Future-From the "2022 GISEA International Symposium".Journal of clinical medicine · 2022Review
- Intrinsic Folding Properties of the HLA-B27 Heavy Chain Revealed by Single Chain Trimer Versions of Peptide-Loaded Class I Major Histocompatibility Complex Molecules.Frontiers in immunology · 2022Article
- Spondyloarthritides: Theories and beyond.Frontiers in pediatrics · 2022Review
- Joint together: The etiology and pathogenesis of ankylosing spondylitis.Frontiers in immunology · 2022Review
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- The enigmatic role of HLA-B*27 in spondyloarthritis pathogenesis.Seminars in immunopathology · 2021Review
- Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview.Frontiers in immunology · 2021Review
- Review
- Unraveling the regulatory role of endoplasmic-reticulum-associated degradation in tumor immunity.Critical reviews in biochemistry and molecular biology · 2020Review
- Endoplasmic reticulum-associated degradation and beyond: The multitasking roles for HRD1 in immune regulation and autoimmunity.Journal of autoimmunity · 2020Review
- Advances in nanomedicine for the treatment of ankylosing spondylitis.International journal of nanomedicine · 2019Review
- Article
- The Role of Autophagy in the Degradation of Misfolded HLA-B27 Heavy Chains.Arthritis & rheumatology (Hoboken, N.J.) · 2018Article
- Pathogenesis of ankylosing spondylitis - recent advances and future directions.Nature reviews. Rheumatology · 2017Review
- Evolution of protein N-glycosylation process in Golgi apparatus which shapes diversity of protein N-glycan structures in plants, animals and fungi.Scientific reports · 2017Article
- The role of the unfolded protein response in axial spondyloarthritis.Clinical rheumatology · 2016Review
- Editorial: HLA-B27: The Story Continues to Unfold.Arthritis & rheumatology (Hoboken, N.J.) · 2016Article
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Authors and funding
17 authors at 7 institutions in 3 countries.
Funding
Abstract
objectiveHLA-B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This study was undertaken to define the role of the UPR-induced ER-associated degradation (ERAD) pathway in the disposal of HLA-B27 dimeric conformers.
methodsHeLa cell lines expressing only 2 copies of a carboxy-terminally Sv5-tagged HLA-B27 were generated. The ER stress-induced protein ER degradation-enhancing α-mannosidase-like protein 1 (EDEM1) was overexpressed by transfection, and dimer levels were monitored by immunoblotting. EDEM1, the UPR-associated transcription factor X-box binding protein 1 (XBP-1), the E3 ubiquitin ligase hydroxymethylglutaryl-coenzyme A reductase degradation 1 (HRD1), and the degradation-associated proteins derlin 1 and derlin 2 were inhibited using either short hairpin RNA or dominant-negative mutants. The UPR-associated ERAD of HLA-B27 was confirmed using ER stress-inducing pharamacologic agents in kinetic and pulse chase assays.
resultsWe demonstrated that UPR-induced machinery can target HLA-B27 dimers and that dimer formation can be controlled by alterations to expression levels of components of the UPR-induced ERAD pathway. HLA-B27 dimers and misfolded major histocompatibility complex class I monomeric molecules bound to EDEM1 were detected, and overexpression of EDEM1 led to inhibition of HLA-B27 dimer formation. EDEM1 inhibition resulted in up-regulation of HLA-B27 dimers, while UPR-induced ERAD of dimers was prevented in the absence of EDEM1. HLA-B27 dimer formation was also enhanced in the absence of XBP-1, HRD1, and derlins 1 and 2.
conclusionThe present findings indicate that the UPR ERAD pathway can dispose of HLA-B27 dimers, thus presenting a potential novel therapeutic target for modulation of HLA-B27-associated inflammatory disease.
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