The SZT2 Interactome Unravels New Functions of the KICSTOR Complex


Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations.


DOI: 10.3390/cells10102711

Projects: MESI-STRAT

Publication type: Journal

Journal: Cells

Citation: Cells 10(10):2711

Date Published: 1st Oct 2021

Registered Mode: by DOI

Authors: Cecilia Cattelani, Dominik Lesiak, Gudrun Liebscher, Isabel I. Singer, Taras Stasyk, Moritz H. Wallnöfer, Alexander M. Heberle, Corrado Corti, Michael W. Hess, Kristian Pfaller, Marcel Kwiatkowski, Peter P. Pramstaller, Andrew A. Hicks, Kathrin Thedieck, Thomas Müller, Lukas A. Huber, Mariana Eca Guimaraes de Araujo

help Submitter
Cattelani, C., Lesiak, D., Liebscher, G., Singer, I. I., Stasyk, T., Wallnöfer, M. H., Heberle, A. M., Corti, C., Hess, M. W., Pfaller, K., Kwiatkowski, M., Pramstaller, P. P., Hicks, A. A., Thedieck, K., Müller, T., Huber, L. A., & Eca Guimaraes de Araujo, M. (2021). The SZT2 Interactome Unravels New Functions of the KICSTOR Complex. In Cells (Vol. 10, Issue 10, p. 2711). MDPI AG.

Views: 37

Created: 15th Mar 2023 at 11:46

Last updated: 15th Mar 2023 at 11:51

help Tags

This item has not yet been tagged.

help Attributions


Powered by
Copyright © 2008 - 2023 The University of Manchester and HITS gGmbH