Ca⁺² and Nε-lysine acetylation regulate the CALR-ATG9A interaction in the lumen of the endoplasmic reticulum.

ABSTRACT: The acetylation of autophagy protein 9 A (ATG9A) in the lumen of the endoplasmic reticulum (ER) by ATase1 and ATase2 regulates the induction of reticulophagy. Analysis of the ER-specific ATG9A interactome identified calreticulin (CALR), an ER luminal Ca⁺²-binding chaperone, as key for ATG9A activity. Specifically, if acetylated, ATG9A is sequestered by CALR and prevented from engaging FAM134B and SEC62. Under this condition, ATG9A is unable to activate the autophagy core machinery. In contrast, when non-acetylated, ATG9A is released by CALR and able to engage FAM134B and SEC62. In this study, we report that Ca⁺² dynamics across the ER membrane regulate the ATG9A-CALR interaction as well as the ability of ATG9A to trigger reticulophagy. We show that the Ca⁺²

SUBMITTER: Braun MM 

PROVIDER: S-EPMC11513142 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature