ArticleCell death and differentiation2019
NFκB mitigates the pathological effects of misfolded α1-antitrypsin by activating autophagy and an integrated program of proteostasis mechanisms.
Article in Cell death and differentiation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Deficient chaperone-mediated autophagy drives multiorgan fibrogenesis via SMAD2/4 stabilization to sustain TGFβ-SMAD signaling.Acta pharmacologica Sinica · 2026Article
- The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50.Nature communications · 2026Article
- α‑1 Antitrypsin is a potential target of inflammation and immunomodulation (Review).Molecular medicine reports · 2025Review
- Spatial covariance reveals isothiocyanate natural products adjust redox stress to restore function in alpha-1-antitrypsin deficiency.Cell reports. Medicine · 2025Article
- Regulation of PGC1α Downstream of the Insulin Signaling Pathway Plays a Role in the Hepatic Proteotoxicity of Mutant α1-Antitrypsin Deficiency Variant Z.Gastroenterology · 2022Article
- Salvianolic acid B inhibits autophagy and activation of hepatic stellate cells induced by TGF-β1 by downregulating the MAPK pathway.Frontiers in pharmacology · 2022Article
- Protein Misfolding and Aggregation: The Relatedness between Parkinson's Disease and Hepatic Endoplasmic Reticulum Storage Disorders.International journal of molecular sciences · 2021Review
- Crosstalk of the IκB Kinase with Spliced X-Box Binding Protein 1 Couples Inflammation with Glucose Metabolic Reprogramming in Epithelial-Mesenchymal Transition.Journal of proteome research · 2021Article
- The molecular species responsible for αThe FEBS journal · 2021Article
- Liver Fibrosis-From Mechanisms of Injury to Modulation of Disease.Frontiers in medicine · 2021Review
- Advances in Alpha-1 Antitrypsin Gene Therapy.American journal of respiratory cell and molecular biology · 2020Review
- Alpha-1 Antitrypsin Deficiency-Mediated Liver Toxicity: Why Do Some Patients Do Poorly? What Do We Know So Far?Chronic obstructive pulmonary diseases (Miami, Fla.) · 2020Review
- MicroRNA-31-5p Exacerbates Lipopolysaccharide-Induced Acute Lung Injury via Inactivating Cab39/AMPKOxidative medicine and cellular longevity · 2020Article
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Authors and funding
6 authors at 2 institutions in 1 country.
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Abstract
Intrahepatocytic accumulation of misfolded α1-antitrypsin Z variant (ATZ) is responsible for liver disease in some individuals with α1-antitrypsin deficiency (ATD), characterized by fibrosis/cirrhosis and predisposition to carcinogenesis. Previous results showing that accumulation of ATZ in model systems activates the NFκB signaling pathway have led us to hypothesize that downstream targets of NFκB are elements of a proteostasis response network for this type of proteinopathy. Here we show that only a subset of downstream targets within the NFκB transcriptomic repertoire are activated in model systems of this proteinopathy. Breeding of the PiZ mouse model of ATD to two different mouse models with NFκB deficiency led to greater intrahepatocytic accumulation of ATZ, more severe hepatic fibrosis, decreased autophagy and hyperproliferation of hepatocytes with massive ATZ inclusions. Specific downstream targets of NFκB could be implicated in each pathological effect. These results suggest a new role for NFκB signaling in which specific downstream targets of this pathway mediate an integrated program of proteostatic responses designed to mitigate the pathologic effects of proteinopathy, including autophagic disposal of misfolded protein, degradation of collagen and prevention of hyperproliferation.
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