Targeting endoplasmic reticulum (ER)-dependent protein degradation could be a promising therapeutic strategy to manage the hepatic consequences of alpha-1 antitrypsin deficiency (AATD), according to a new study published in Frontiers in Molecular Biosciences.

ER-mediated degradative processes are important to maintain proteostasis, being considered driver events in AATD pathogenesis. Alpha-1 antitrypsin (AAT) PI-Z aggregates tend to accumulate in the ER of hepatocytes, contributing to ER stress and liver disease.

In turn, hepatocytes make use of cellular processes, such as ER-associated degradation (ERAD) and ER lysosomal-associated degradation (ERLAD), in an attempt to control the accumulation of AAT aggregates. The selected process depends on the state of the PI-Z mutant proteins.


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“Numerous groups have described that both ERAD and ERLAD are highly involved in reducing the liver burden during AAT aggregate accumulation within the ER of hepatocytes,” Caroline Duwaerts, PhD, and Jessica Maiers, PhD, said. “ERAD being favored when aggregates remain small and soluble while ERLAD is used when aggregates are large and insoluble.”

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The involvement of ERAD in the degradation of PI-Z aggregates is complex. Evidence suggests that it involves several mediators, including calnexin, the complex VCP/p97-AMFR/GP78, the E3 ubiquitin ligase HRD1/SYNV1, ER resident lectins, and chaperones, among others. The presence of ERAD-resistant, insoluble aggregates in hepatocytes dictates the shift towards ERLAD. ERLAD can be subdivided into 3 main categories: autophagosomal (macro-ER-phagy), endolysosomal (micro-ER-phagy), or lysosomal (vesicular delivery).

Although some studies had identified a number of molecules involved in ERLAD-mediated PI-Z aggregates degradation during AATD, the complete scenario remains to be elucidated. However, a better understanding of the autophagic and ER-phagic pathways could have a positive impact on the development of new therapeutic strategies for AATD.

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“The role of autophagy and macro-ER-phagy in PI-Z degradation led to numerous groups testing autophagic drugs in order to reduce hepatocyte aggregates and reduce the liver burden of AATD,” Drs. Duwaerts and Maiers concluded. The drugs include carbamazepine, rapamycin, ezetimibe, nor-ursodeoxycholic acid, and glibenclamide, which positively regulate autophagy.

Reference

Duwaerts CC, Maiers JL. ER disposal pathways in chronic liver disease: protective, pathogenic, and potential therapeutic targets. Front Mol Biosci. 2022;8:804097. doi:10.3389/fmolb.2021.804097