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Cattelani C, Lesiak D, Liebscher G, et al. The SZT2 Interactome Unravels New Functions of the KICSTOR Complex. Cells. 2021;10(10)doi: 10.3390/cells10102711.
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. Cells, 10(10), . https://doi.org/10.3390/cells10102711
Cattelani, Cecilia, et al. "The SZT2 Interactome Unravels New Functions of the KICSTOR Complex." Cells vol. 10,10 (2021). doi: https://doi.org/10.3390/cells10102711
Cattelani C, Lesiak D, Liebscher G, Singer II, Stasyk T, Wallnöfer MH, Heberle AM, Corti C, Hess MW, Pfaller K, Kwiatkowski M, Pramstaller PP, Hicks AA, Thedieck K, Müller T, Huber LA, Eca Guimaraes de Araujo M. The SZT2 Interactome Unravels New Functions of the KICSTOR Complex. Cells. 2021 Oct 09;10(10). doi: 10.3390/cells10102711. PMID: 34685691; PMCID: PMC8534408.
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Cells. 2021 Oct 09;10(10). doi: 10.3390/cells10102711.

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex.

Cells

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

Affiliations

  1. Institute of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  2. Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy.
  3. Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, 6020 Innsbruck, Austria.
  4. Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
  5. Institute of Histology and Embryology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  6. Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany.
  7. Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  8. Austrian Drug Screening Institute, ADSI, 6020 Innsbruck, Austria.

PMID: 34685691 PMCID: PMC8534408 DOI: 10.3390/cells10102711

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.

Keywords: KICSTOR; SZT2; autophagy; ciliogenesis; epilepsy; mTORC1; neurodegeneration; neurogenesis

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