PXD027662

PXD027662 is an original dataset announced via ProteomeXchange.

Title	Proteomics analysis unravels new functions of the KICSTOR component SZT2
Description	Developmental and epileptic encephalopathy is a group of rare, severe neurodevelopmental disorders characterized by the co-occurrence of epilepsy and intellectual disability (ID), in which there is additional developmental impairment independent of epileptic activity. In 2009, through a chemical mutagenesis screen performed in mice, it was found that mutations in Seizure threshold 2 (SZT2) trigger a higher susceptibility to seizures in a semidominant manner. Since then 27 patients have been identified with biallelic SZT2 mutations (in compound heterozygous or homozygous state), all of them displaying developmental delay of varying severity and dysmorphic features such as macrocephaly. Patients commonly suffer from recurrent epileptic seizures that often are refractory to available therapies. Human SZT2 encodes a 3,375 amino acids protein highly conserved throughout evolution, that is predominantly expressed in embryonal stages and in the adult the brain. The molecular functions of SZT2 protein are largely unknown however it has been reported that SZT2 forms a complex with KPTN, ITFG2, and C12orf66. This complex, named KICSTOR, senses aminoacid depletion and functions as a negative regulator of mTORC1 under catabolic conditions. Taking into consideration that SZT2 remain one of the least characterized regulators of mTORC1 we decided to decipher its interactome under catabolic and anabolic conditions. We found mTORC1 and AMPK signaling components enriched in the SZT2 interactome, but also prominent clusters of autophagy and ciliogenesis regulators as well as a significant number of hits that regulate neurogenesis and neurodegenerative processes. We have validated a few key hits from the interactome, including proteins involved in cilliogenesis and epilepsy. The detailed analysis of the SZT2KOs demonstrated that although these cells show increased mTORC1 signaling that can be prevented by treatment with either rapamycin or torin, they also contra intuitively display increased autophagy that is independent of the physiological conditions tested. These results are in accordance with our interactome data were we detect a significant pool of selective autophagy receptors/regulators. Overall the presented data should serve as a tool to address the physiological functions of SZT2 in more comprehensive manner. In the manuscript discussion we put forward our model in which SZT2 plays a broader role in the coordination of cellular metabolism than previously anticipated.
HostingRepository	PRIDE
AnnounceDate	2021-11-02
AnnouncementXML	Submission_2021-11-02_04:37:55.110.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mariana Eca Guimaraes de Araujo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-30 03:44:01	ID requested
⏵ 1	2021-11-02 04:37:55	announced

Dataset with its publication pending

submitter keyword: SZT2, KICSTOR, mTORC1, lysosome

Mariana Eca Guimaraes de Araujo
contact affiliation	Div. Cell Biology, Biocenter, Medical University Innsbruck, Austria
contact email	mariana.araujo@i-med.ac.at
lab head
Mariana Eca Guimaraes de Araujo
contact affiliation	Medical University Innsbruck, Biocenter, Division of Cell Biology
contact email	mariana.araujo@i-med.ac.at
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/11/PXD027662

PRIDE project URI

• PRIDE
  1. PXD027662
     1. Label: PRIDE project
     2. Name: Proteomics analysis unravels new functions of the KICSTOR component SZT2