The molecular species responsible for α₁‐antitrypsin deficiency are suppressed by a small molecule chaperone

Abstract

The formation of ordered Z α1‐antitrypsin polymers is central to liver disease in α1‐antitrypsin deficiency. The nascent α1‐antitrypsin folds via the M* intermediate to native monomer or becomes incorporated into a soluble polymer that can be secreted, degraded or precipitate as insoluble inclusions. We describe the kinetics of the clearance of Z α1‐antitrypsin polymers and show that they can be abolished with a small molecule preventing the formation of M*.

The Recruitment-Secretory Block (“R-SB”) Phenomenon and Endoplasmic Reticulum Storage Diseases

“…The simultaneous retention of abnormal fibrinogen and normal lipoprotein molecules appear to share some analogy with the divergent behavior of M and Z AAT fraction as reflected into the "R-SB" phenomenon, and at the same time with the recent observations showing that about 6% of the normal M AAT can make heteropolymers with the Z AAT in the RER [28] and that these heteropolymers can be found in circulation [28,29,44,45].…”

N‐glycan processing selects ERAD‐resistant misfolded proteins for ER‐to‐lysosome‐associated degradation

“…The Z mutation (blue in Fig 1B ) enhances formation of ERAD‐resistant polymers, which are delivered to lysosomal compartments for clearance both in mammalian and in yeast cells (Teckman & Perlmutter, 2000 ; Kamimoto et al , 2006 ; Kroeger et al , 2009 ; Hidvegi et al , 2010 ; Perlmutter, 2011 ; Pastore et al , 2013 ; Yamamura et al , 2014 ; Fregno et al , 2018 ; Cui et al , 2019 ; Strnad et al , 2020 ). ATZ NNN polymers are recognized by the monoclonal antibody 2C1 (Miranda et al , 2010 ; Ronzoni et al , 2021 ). They are transported from the ER to degradative endolysosomal compartments, where they accumulate upon inhibition of lysosomal hydrolases (Fregno et al , 2018 ).…”

The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant

“…Polymer formation was first assessed by the tendency of the variants to accumulate as intracellular aggregates not solubilized by NP-40 treatment. As recently described [ 20 ], the partitioning of intracellular AAT between soluble and insoluble fractions after lysis in the presence of non-ionic NP-40 detergent at 1% v / v concentration represents a simple and reliable method to assess the tendency of AAT variants to polymerize and accumulate within inclusion bodies.…”

“…Protein folding and aggregation are dynamic, kinetic processes, and as such relative differences in misfolding, deposition, degradation and secretion can have pronounced effects on molecular fate [ 20 , 50 ]. To investigate the kinetics of intracellular polymer accumulation and their consequences for secretion, we performed pulse-chase experiments on Hepa 1.6 cells transfected with the panel of AAT variants.…”

“…Polymers of Z AAT have also been found in the circulation [ 16 ] and in the lung interstitium [ 17 ], where they are thought to stimulate chemotactic recruitment and degranulation of neutrophils, thus amplifying tissue damage of the lung parenchyma and the progression to emphysema [ 18 ]. Extracellular polymers have been shown to derive from active cell secretion rather than being released by cell death or formed by extracellular polymerization of secreted monomeric protein [ 19 , 20 ].…”