ATG9A regulates proteostasis through reticulophagy receptors FAM134B and SEC62 and folding chaperones CALR and HSPB1
Brendan K. Sheehan,
Nicola S. Orefice,
Yajing Peng,
Samantha L. Shapiro,
Luigi Puglielli
Affiliations
Brendan K. Sheehan
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Nicola S. Orefice
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Yajing Peng
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Samantha L. Shapiro
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Luigi Puglielli
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, WI 53705, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA; Corresponding author
Summary: The acetylation of ATG9A within the endoplasmic reticulum (ER) lumen regulates the induction of reticulophagy. ER acetylation is ensured by AT-1/SLC33A1, a membrane transporter that maintains the cytosol-to-ER flux of acetyl-CoA. Defective AT-1 activity, as caused by heterozygous/homozygous mutations and gene duplication events, results in severe disease phenotypes. Here, we show that although the acetylation of ATG9A occurs in the ER lumen, the induction of reticulophagy requires ATG9A to engage FAM134B and SEC62 on the cytosolic side of the ER. To address this conundrum, we resolved the ATG9A interactome in two mouse models of AT-1 dysregulation: AT-1 sTg, a model of systemic AT-1 overexpression with hyperacetylation of ATG9A, and AT-1S113R/+, a model of AT-1 haploinsufficiency with hypoacetylation of ATG9A. We identified CALR and HSPB1 as two ATG9A partners that regulate the induction of reticulophagy as a function of ATG9A acetylation and discovered that ATG9A associates with several proteins that maintain ER proteostasis.
