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Nup358 restricts ER-mitochondria connectivity by modulating mTORC2/Akt/GSK3β signalling
Misha Kalarikkal1, Rimpi Saikia1, Lizanne Oliveira1
1National Centre for Cell Science, S.P. Pune University Campus, Pune, Maharashtra, 411007, India.
EMBO Reports
|July 18, 2024
Summary
Annulate lamellae (AL) proteins, like Nup358, regulate endoplasmic reticulum-mitochondria contact sites (ERMCSs). Nup358 depletion enhances ERMCSs by modulating the mTORC2/Akt/GSK3β pathway, revealing a new control mechanism.
Area of Science:
- Cell Biology
- Molecular Biology
- Organelle Biology
Background:
- Endoplasmic reticulum-mitochondria contact sites (ERMCSs) are crucial for cellular functions like calcium homeostasis and metabolism.
- While mTORC2/Akt stabilizes ERMCSs and GSK3β reduces their connectivity, the precise regulatory mechanisms remain unclear.
- Annulate lamellae (AL), ER subdomains containing nucleoporins, have not been previously linked to ERMCS regulation.
Purpose of the Study:
- To investigate the role of annulate lamellae (AL) and their resident nucleoporins in regulating ER-mitochondria contact sites (ERMCSs).
- To elucidate the molecular mechanisms by which nucleoporins control ERMCSs, focusing on the mTORC2/Akt/GSK3β signaling axis.
Main Methods:
- Depletion of Nup358 (an AL nucleoporin) and Rictor (an mTORC2 subunit) using siRNA.
- Analysis of ER-mitochondria connectivity and mTORC2/Akt/GSK3β signaling pathway activation.
- Expression of a Nup358 fragment to assess its functional role in VAPB-PTPIP51 complex interaction.
Main Results:
- Depletion of Nup358 led to increased ERMCSs, enhanced mTORC2/Akt activation, and GSK3β inhibition.
- Rictor depletion or exogenous GSK3β expression reversed the ERMCS phenotype in Nup358-deficient cells.
- Nup358 directly interacts with the VAPB-PTPIP51 complex, restricting mTORC2/Akt signaling and ERMCS connectivity.
Conclusions:
- Nup358, localized to annulate lamellae at ERMCSs, acts as a novel regulator of ER-mitochondria connectivity.
- Nup358 controls ERMCSs by modulating the mTORC2/Akt/GSK3β signaling axis.
- This study uncovers a previously unrecognized mechanism for ERMCS regulation involving nucleoporins.
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