Alcohol‐Induced Liver Injury: Down‐regulation and Redistribution of Rab3D Results in Atypical Protein Trafficking

• DOI: 10.1002/hep4.1811
• Publication Date: 2021-09-08T02:04:15Z
• Authors: Carol A. Casey; Amanda J. Macke; Ryan R. Gough; Artem N. Pachikov; Mary E. Morris; Paul G. Thomes; Jacy L. Kubik; Melissa S. Holzapfel; Armen Petrosyan
• Keywords: COPI; COPII

Previous work from our laboratories has identified multiple defects in endocytosis, protein trafficking, and secretion, along with altered Golgi function after alcohol administration. Manifestation of alcohol‐associated liver disease (ALD) is associated an aberrant several hepatic proteins, including asialoglycoprotein receptor (ASGP‐R), their atypical distribution at the plasma membrane (PM), secretion abnormally glycosylated forms into bloodstream, but trafficking mechanism unknown. Here we report that a small GTPase, Rab3D, known to be involved exocytosis, vesicle shows ethanol (EtOH)–impaired function, which plays important role disorganization. We used approaches cellular/animal models ALD, Rab3D knockout (KO) mice human tissue patients ALD. found resides primarily trans ‐ cis ‐faces Golgi; however, EtOH treatment results redistribution tran s‐Golgi cis‐medial‐ Golgi. Cells lacking demonstrate enlargement Golgi, especially its distal compartments. required for coat I (COPI) vesiculation conversely, COPI critical intra‐Golgi Rab3D. Rab3D/COPI association was not only ALD also donors consuming without steatosis. In KO mice, hepatocytes experience endoplasmic reticulum (ER) stress, administration activates apoptosis. Notably, these cells, ASGP‐R, despite incomplete glycosylation, can still reach cell surface through ER‐PM junctions. This mimics effects seen EtOH‐induced injury. Conclusion : revealed down‐regulation contributes significantly disorganization, ASGP‐R excreted connections, bypassing canonical (ER→Golgi→PM) anterograde transportation. suggests sites may therapeutic target