The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization

Dengjel, J.; Siva Sankar, D.; Kaeser-Pebernard, S.; Vionnet, C.; Favre, S.; Oliveira De Marchioro, L.; Pillet, B.; Zhou, J.; Kovacs, W. J.; Kressler, D.; Antonioli, M.; Fimia, G. M.

doi:10.1101/2023.12.08.570815

bioRxiv · 10.1101/2023.12.08.570815

The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization

Dengjel, J.·Siva Sankar, D.·Kaeser-Pebernard, S.·Vionnet, C.·Favre, S.·Oliveira De Marchioro, L.·Pillet, B.·Zhou, J.·Kovacs, W. J.·Kressler, D.·Antonioli, M.·Fimia, G. M.

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Abstract

Canonical autophagy is regulated by ULK1, the most proximal protein kinase specifically regulating autophagy initiation. To gain new insights into functions of the ULK1 holo-complex in autophagy regulation, we generated a deep ULK1 complex interactome by combining affinity purification- and proximity labelling-mass spectrometry of all four ULK1 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, also several selective autophagy receptors 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 promoting conditions, the unphosphorylated form of BAG2 sequesters AMBRA1, attenuating autophagy induction. In starvation conditions, ULK1 phosphorylates BAG2 on Ser31, supporting its recruitment to the ER membrane and positively affecting autophagy flux.

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Dengjel, J., Siva Sankar, D., Kaeser-Pebernard, S., Vionnet, C., Favre, S., Oliveira De Marchioro, L., Pillet, B., Zhou, J., Kovacs, W. J., Kressler, D., Antonioli, M., Fimia, G. M.. 2023-12-09. The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization. https://doi.org/10.1101/2023.12.08.570815

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