The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

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

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    Abstract

    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.

    Original languageEnglish
    Article number2711
    Number of pages30
    JournalCells
    Volume10
    Issue number10
    DOIs
    Publication statusPublished - 9-Oct-2021

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