Autophagy initiation is regulated by the ULK1 kinase complex. To gain insights into functions of the holocomplex, we generated a deep interactome by combining affinity purification- and proximity labeling- mass spectrometry of all four complex members: ULK1, ATG13, ATG101, and RB1CC1/FIP200. Under starvation conditions, the ULK1 complex interacts with several protein and lipid kinases and phosphatases, implying the formation of a signalosome. Interestingly, several selective autophagy receptors also interact with ULK1, indicating the activation of selective autophagy pathways by nutrient starvation. One effector of the ULK1 complex is the HSC/HSP70 co-chaperone BAG2, which regulates the subcellular localization of the VPS34 lipid kinase complex member AMBRA1. Depending on the nutritional status, BAG2 has opposing roles. In growth conditions, the unphosphorylated form of BAG2 sequesters AMBRA1, attenuating autophagy induction. In starvation conditions, ULK1 phosphorylates BAG2 on Ser31, which supports the recruitment of AMBRA1 to the ER membrane, positively affecting autophagy.
Sankar, D.s., Kaeser-Pebernard, S., Vionnet, C., Favre, S., de Oliveira Marchioro, L., Pillet, B., et al. (2024). The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization. CELL REPORTS, 43(9) [10.1016/j.celrep.2024.114689].
The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization
Antonioli, Manuela;
2024-09-24
Abstract
Autophagy initiation is regulated by the ULK1 kinase complex. To gain insights into functions of the holocomplex, we generated a deep interactome by combining affinity purification- and proximity labeling- mass spectrometry of all four complex members: ULK1, ATG13, ATG101, and RB1CC1/FIP200. Under starvation conditions, the ULK1 complex interacts with several protein and lipid kinases and phosphatases, implying the formation of a signalosome. Interestingly, several selective autophagy receptors also interact with ULK1, indicating the activation of selective autophagy pathways by nutrient starvation. One effector of the ULK1 complex is the HSC/HSP70 co-chaperone BAG2, which regulates the subcellular localization of the VPS34 lipid kinase complex member AMBRA1. Depending on the nutritional status, BAG2 has opposing roles. In growth conditions, the unphosphorylated form of BAG2 sequesters AMBRA1, attenuating autophagy induction. In starvation conditions, ULK1 phosphorylates BAG2 on Ser31, which supports the recruitment of AMBRA1 to the ER membrane, positively affecting autophagy.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
