Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis

Tracing genetic diversity captures the molecular basis of misfolding disease

“…We recently showed that pharmacological activation of ATF6, a specific branch of the unfolded protein response (UPR) pathway that regulates the proteostasis environment in the ER, can improve the function of AAT variants while simultaneously reducing aggregation in the ER 34 . Preliminary results suggested that ER chaperones GRP78 and GRP94 are required for the restoration of function impacted by ATF6 activators 34 . As a paralog of the cytosolic Hsp90, GRP94 is a highly abundant ATP-dependent chaperone found in the ER 14,16,[42][43][44] .…”

“…AAT is synthesized and secreted from hepatocytes for delivery to the lung at grams per day where it binds human neutrophil elastase (NE) and prevents NE-induced degradation of the extracellular matrix (ECM) in the lung 30,31 . Numerous variants in the AAT protein can cause protein misfolding during nascent synthesis in the ER, the first step of the secretory pathway [32][33][34] , leading to aggregation with extended polymers that trigger liver disease phenotypes, such as fibrosis, cirrhosis and hepatocellular carcinoma [35][36][37] . AAT aggregation in the liver results in reduced secretion of functional AAT to the plasma, leading to a loss-of-function in the lung manifested as the inflammatory diseases emphysema, bronchitis and COPD 30,38 .…”

“…GP-SCV principled relationships reveal the impact of GPR94 ATPase activity to (re)direct the N-to C-terminal cooperative folding of AAT to correct AATD clinical phenotypes impacting both liver and lung disease. We suggest that GP-SCV principled relationships provide a standard computational framework to address information flow from the genome to proteome affecting protein fold conversion by a broad range of proteostasis components affecting health and disease on a residue-byresidue basis 1,20,21,34 , providing a precision approach to mitigate disease.…”

Divergent Proteome Reactivity Influences Arm-Selective Activation of the Unfolded Protein Response by Pharmacological Endoplasmic Reticulum Proteostasis Regulators

“…We previously conducted a cell-based high-throughput screen to identify selective activators of ATF6 signaling . From this screen, N -(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (AA147; Figure A) emerged as a selective ATF6 activator that is able to promote adaptive ATF6 activity to mitigate pathologies associated with etiologically diverse disorders. ,− We found that AA147 functions as a prodrug, wherein the oxidative conversion of the 2-amino- p -cresol substructure by ER-resident oxidases (e.g., cytochrome P450s) leads to an electrophilic quinone methide that covalently engages a subset of ER proteins primarily consisting of protein disulfide isomerases (PDIs) . PDIs maintain ATF6 in disulfide-bonded oligomeric structures that restrain its activation. − This suggested that AA147-dependent modification of a subset of PDIs could lead to reduction, monomerization, and subsequent trafficking of ATF6 to the Golgi, where S1/S2-enabled proteolytic cleavage affords the cytosolic ATF6 transcription factor amenable to nuclear localization and transcriptional remodeling.…”

“… 19 From this screen, N -(2-hydroxy-5-methylphenyl)-3-phenylpropanamide (AA147; Figure 1 A) emerged as a selective ATF6 activator that is able to promote adaptive ATF6 activity to mitigate pathologies associated with etiologically diverse disorders. 11 , 19 − 26 We found that AA147 functions as a prodrug, wherein the oxidative conversion of the 2-amino- p -cresol substructure by ER-resident oxidases (e.g., cytochrome P450s) leads to an electrophilic quinone methide that covalently engages a subset of ER proteins primarily consisting of protein disulfide isomerases (PDIs). 27 PDIs maintain ATF6 in disulfide-bonded oligomeric structures that restrain its activation.…”