ArticleThe Journal of biological chemistry2009
Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 142 citations in OpenAlex.
- Polymerized Z-α-1 antitrypsin leads to lung injury in a murine model of emphysema.JCI insight · 2026Article
- SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The role of N-glycans and their processing in ER-to-lysosome-associated degradation of disease-causing mutant Neuroserpin.Autophagy reports · 2026Article
- Autophagy in cancer and protein conformational disorders.FEBS letters · 2025Review
- Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing.Molecular therapy. Nucleic acids · 2025Article
- An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIB.Drug development research · 2025Article
- Protocol for iterative enrichment of integrated sgRNAs via derivative CRISPR-Cas9 libraries from genomic DNA of sorted fixed cells.STAR protocols · 2024Article
- Different ER-plasma membrane tethers play opposing roles in autophagy of the cortical ER.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- ER-to-lysosome-associated degradation acts as failsafe mechanism upon ERAD dysfunction.EMBO reports · 2024Article
- SERPINC1 c.1247dupC: a novel SERPINC1 gene mutation associated with familial thrombosis results in a secretion defect and quantitative antithrombin deficiency.Thrombosis journal · 2024Article
- Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy.Hepatology communications · 2024Article
- Neuroserpin gene therapy inhibits retinal ganglion cell apoptosis and promotes functional preservation in glaucoma.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Expression of the Z Variant of α1-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish.International journal of molecular sciences · 2023Article
- Full-length antithrombin frameshift variant with aberrant C-terminus causes endoplasmic reticulum retention with a dominant-negative effect.JCI insight · 2022Article
- Keratin 8 is a scaffolding and regulatory protein of ERAD complexes.Cellular and molecular life sciences : CMLS · 2022Article
- Elucidating the pathological mechanisms of neurodegeneration in the lethal serpinopathy FENIB.Neural regeneration research · 2022Article
- Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB.Cellular and molecular life sciences : CMLS · 2022Article
- ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum.Physiological reviews · 2022Review
- Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell-cell interactions in the pathophysiology of neurological disease.Cellular and molecular life sciences : CMLS · 2022Review
- ER-phagy requires the assembly of actin at sites of contact between the cortical ER and endocytic pits.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
13 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
The serpinopathies are a family of diseases characterized by the accumulation of ordered polymers of mutant protein within the endoplasmic reticulum. They are a diverse group including alpha(1)-antitrypsin deficiency and the inherited dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. We have used transient transfection of COS7 cells and mouse embryonic fibroblasts, PC12 cell lines that conditionally express wild type and mutant neuroserpin and fly models of FENIB to assess the cellular handling of wild type and mutant serpins. By using a polymer-specific monoclonal antibody, we show that mutant neuroserpin forms polymers after a delay of at least 30 min and that polymers can be cleared in PC12 cell lines and from the brain in a fly model of FENIB. At steady state, the fractions of intracellular polymerogenic G392E mutant neuroserpin in the monomeric and polymeric states are comparable. Inhibition of the proteasome with MG132 reveals that both mutant neuroserpin and alpha(1)-antitrypsin are degraded predominantly by endoplasmic reticulum-associated degradation (ERAD). Pharmacological and genetic inhibitions demonstrate that autophagy is responsible for bulk turnover of wild type and mutant serpins, but can be stimulated by rapamycin to compensate for proteasome inhibition. The significance of these findings to the treatment of serpinopathies is discussed.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.