The unc-51 like autophagy activating kinase 1-autophagy related 13 complex has distinct functions in tunicamycin-treated cells.

Abstract

Endoplasmic reticulum (ER) stress and autophagy are regulated by shared signaling pathways, and their dysfunction is directly related to pathological conditions. This study investigated the function of the unc-51 like autophagy activating kinase 1 (ULK1)-autophagy related 13 (ATG13) complex in ER stress conditions through a knockout (KO) approach. Unlike other autophagy genes, KO of ULK1 or ATG13 attenuated ER stress and promoted mammalian target of rapamycin complex 1 (mTORC1) activation. Compared with wild type (WT) cells, ULK1 and ATG13 KO cells displayed increased viability, while beclin 1, ATG14, and ULK1/2 KO cells did not. Tunicamycin treatment upregulated the expression of ER stress markers (DNA damage inducible transcript 3, heat shock protein family A (Hsp70) member 5, and phosphorylated eukaryotic translation initiation factor 2 alpha kinase 3, eukaryotic translation initiation factor 2 subunit alpha, and endoplasmic reticulum to nucleus signaling 1); however, these were decreased in ULK1 and ATG13 KO cells. Insulin treatment upregulates the phosphorylation of ribosomal protein S6 kinase B1 (RPS6KB1) and AKT serine/threonine kinase 1 (AKT1), which was suppressed by tunicamycin. Notably, ATG13 and ULK1 deficiency ameliorated tunicamycin-induced insulin resistance, with enhanced RPS6KB1 and AKT1 phosphorylation in KO cells compared to WT cells. Although ULK1 and ATG13 are necessary for autophagy induction after tunicamycin-induced ER stress, autophagy does not seem to directly affect tunicamycin-induced cell death, ER stress, or insulin resistance. Our results indicate that loss of the ULK1-ATG13 complex attenuates ER stress and cell death and increases mTORC1 signaling.

• Authors: Minji Woo, Hyun-Il Choi, So-Hyun Park, Jiyun Ahn, Young-Jin Jang, Tae-Youl Ha, Dae-Hee Lee, Hyo-Deok Seo, Chang Hwa Jung
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 524 Issue 3 Pg. 744-749 (04 09 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32035621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• ATG13 protein, human
• Autophagy-Related Proteins
• Insulin
• Intracellular Signaling Peptides and Proteins
• Tunicamycin
• Autophagy-Related Protein-1 Homolog
• ULK1 protein, human

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Autophagy-Related Protein-1 Homolog (metabolism)
• Autophagy-Related Proteins (metabolism)
• Cell Survival (drug effects)
• Endoplasmic Reticulum Stress
• HCT116 Cells
• Humans
• Insulin (pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mice
• Tunicamycin (pharmacology)