PXD043611-1

PXD043611 is an original dataset announced via ProteomeXchange.

Title	mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes
Description	To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).
HostingRepository	PRIDE
AnnounceDate	2024-11-26
AnnouncementXML	Submission_2024-11-26_05:40:55.466.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harmjan Vos
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-07 14:40:21	ID requested
⏵ 1	2024-11-26 05:40:55	announced

10.1016/J.MOLCEL.2024.10.009;

submitter keyword: mTORC1/amino acids/lysosomes/Rag GTPases/TFE3/TSC2

Fried J.T.
contact affiliation	Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
contact email	G.J.T.Zwartkruis@umcutrecht.nl
lab head
Harmjan Vos
contact affiliation	University Medical Center Utrecht Dept. Molecular Cancer Research
contact email	h.r.vos-3@umcutrecht.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043611
     1. Label: PRIDE project
     2. Name: mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes