mTORC1 controls Golgi architecture and vesicle secretion by phosphorylation of SCYL1

Stéphanie Kaeser-Pebernard, Christine Vionnet, Muriel Mari, Devanarayanan Siva Sankar, Zehan Hu, Carole Roubaty, Esther Martínez-Martínez, Huiyuan Zhao, Miguel Spuch-Calvar, Alke Petri-Fink, Gregor Rainer, Florian Steinberg, Fulvio Reggiori and Jörn Dengjel ()
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Stéphanie Kaeser-Pebernard: University of Fribourg
Christine Vionnet: University of Fribourg
Muriel Mari: University of Groningen, University Medical Center Groningen
Devanarayanan Siva Sankar: University of Fribourg
Zehan Hu: University of Fribourg
Carole Roubaty: University of Fribourg
Esther Martínez-Martínez: University of Fribourg
Huiyuan Zhao: University of Fribourg
Miguel Spuch-Calvar: University of Fribourg
Alke Petri-Fink: University of Fribourg
Gregor Rainer: University of Fribourg
Florian Steinberg: University of Freiburg
Fulvio Reggiori: University of Groningen, University Medical Center Groningen
Jörn Dengjel: University of Fribourg

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and proliferation, supporting anabolic reactions and inhibiting catabolic pathways like autophagy. Its hyperactivation is a frequent event in cancer promoting tumor cell proliferation. Several intracellular membrane-associated mTORC1 pools have been identified, linking its function to distinct subcellular localizations. Here, we characterize the N-terminal kinase-like protein SCYL1 as a Golgi-localized target through which mTORC1 controls organelle distribution and extracellular vesicle secretion in breast cancer cells. Under growth conditions, SCYL1 is phosphorylated by mTORC1 on Ser754, supporting Golgi localization. Upon mTORC1 inhibition, Ser754 dephosphorylation leads to SCYL1 displacement to endosomes. Peripheral, dephosphorylated SCYL1 causes Golgi enlargement, redistribution of early and late endosomes and increased extracellular vesicle release. Thus, the mTORC1-controlled phosphorylation status of SCYL1 is an important determinant regulating subcellular distribution and function of endolysosomal compartments. It may also explain the pathophysiology underlying human genetic diseases such as CALFAN syndrome, which is caused by loss-of-function of SCYL1.

Date: 2022
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DOI: 10.1038/s41467-022-32487-7

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