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Dynamics of CLIMP-63 S-acylation control ER morphology
Patrick A Sandoz1, Robin A Denhardt-Eriksson2, Laurence Abrami1
1Global Health Institute, School of Life Sciences, EPFL, Lausanne, Switzerland.
Nature Communications
|January 17, 2023
Summary
S-acylation, a lipid modification, regulates cytoskeleton-linking membrane protein 63 (CLIMP-63) to control endoplasmic reticulum (ER) sheet structure. This study reveals how CLIMP-63 acylation-deacylation dynamics shape ER architecture.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The endoplasmic reticulum (ER) possesses a complex, dynamic nanoscale architecture, including sheets and tubular networks.
- Cytoskeleton-linking membrane protein 63 (CLIMP-63) is crucial for ER sheet formation, but its regulatory mechanisms are unclear.
Purpose of the Study:
- To investigate the impact of S-acylation, a lipid modification, on CLIMP-63's cellular distribution and function.
- To elucidate the CLIMP-63 life cycle and its role in ER structure.
Main Methods:
- Native mass spectrometry and kinetic analysis of acylation/deacylation.
- Data-driven mathematical modeling.
- Super-resolution microscopy and focused ion beam electron microscopy.
Main Results:
- CLIMP-63 forms trimeric units in the ER, with some reaching the plasma membrane.
- The majority of CLIMP-63 undergoes S-acylation by ZDHHC6 in the ER, forming stable super-complexes.
- CLIMP-63 acylation-deacylation dynamically controls ER sheet abundance and fenestration.
Conclusions:
- S-acylation is a key post-translational modification regulating CLIMP-63.
- CLIMP-63 acylation-deacylation is a novel mechanism for dynamic lipid post-translational regulation of ER architecture.
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