Multiple Genes Core to ERAD, Macroautophagy and Lysosomal Degradation Pathways Participate in the Proteostasis Response in α1-Antitrypsin Deficiency

• DOI: 10.1016/j.jcmgh.2024.02.006
• Publication Date: 2024-02-07T17:38:06Z
• Authors: Jie Li; Francesca Moretti; Tunda Hidvegi; Sanja Sviben; James A.J. Fitzpa...; Hemalatha Sundara...; Stephen C. Pak; Gary A. Silverman; Britta Knapp; Ireos Filipuzzi; John Alford; John Reece-Hoyes; Florian Nigsch; Leon O. Murphy; Beat Nyfeler; David H. Perlmutter
• Keywords: Proteostasis; Endoplasmic-reticulum-associated protein degradation

Background: In the classical form of α1-antitrypsin deficiency (ATD), misfolded Z (ATZ) variant accumulates in endoplasmic reticulum (ER) liver cells.A gain-of-function proteotoxic mechanism is responsible for chronic disease a sub-group homozygotes.Proteostatic response pathways, including conventional ERAD and autophagy, have been proposed as mechanisms that allow cellular adaptation presumably protection from phenotype.Recent studies concluded distinct lysosomal pathway called ERLAD completely supplants role macro-autophagy degradation ATZ.Here we used several stateof-the-art approaches to more fully characterize proteostatic responses systems model ATD.Methods: We CRISPR-mediated genome editing coupled cell selection step by FACS carry out screening proteostasis genes regulate ATZ accumulation combined with selective two other systems.Results: are key early regulators multiple autophagy genes, well newly described ER-phagy participate manner temporally regulated evolves persists.Time-dependent changes gene expression accompanied specific ultrastructural dilation ER, formation globular inclusions, budding autophagic vesicles alterations overall shape component parts mitochondria.Conclusions: Macro-autophagy critical it becomes important over time synthesis continues unabated.Multiple sub-types non-autophagic degradative pathways needed respond high concentrations protein characterizes ATD these attractive candidates genetic variants predispose hepatic phenotype.