p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.
Pastore Nunzia, Attanasio Sergio, Annunziata Francesco, D'Agostino Claudia, Maffia Veronica, Colonna Rita, Giuliano Teresa, Ferriero Rosa, Boffa Iolanda, Palmer Donna, Ng Philip, De Cegli Rossella, D'Agostino Massimo, Rosenberger Florian, Strnad Pavel, Chambers Joseph E, Marciniak Stefan J, Teckman Jeffrey, Piccolo Pasquale, Brunetti-Pierri Nicola
Abstract
Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients were both found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis, consistent with previous reports. However, whether p62/SQSTM1 is a marker of Z-AAT globules or plays an active role in Z-AAT proteostasis is unclear. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.
Key Findings
- p62/SQSTM1 decorates ubiquitin-positive Z-AAT globules and interacts with Z-AAT at the ER-cytosol interface.
- Genetic ablation of p62/SQSTM1 in PiZ mice reduces hepatic Z-AAT globules, polymers, and serum Z-AAT levels.
- KEAP1 binds to the p62/SQSTM1-Z-AAT complex, leading to NRF2 nuclear translocation and activation, linking Z-AAT accumulation to NRF2 pathway activation.
Clinical Significance
This study highlights the role of p62/SQSTM1 in Z-AAT proteostasis and liver disease pathogenesis in Alpha-1 antitrypsin deficiency, suggesting that targeting the p62/SQSTM1-KEAP1-NRF2 axis could offer therapeutic potential for managing liver proteotoxicity.
Citation
Pastore Nunzia, Attanasio Sergio, Annunziata Francescoet al.. p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity. The Journal of biological chemistry. 2026-Aug-07.