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Role of S-Acylation of Proteins in the Secretory Pathway: Focus on CLIMP-63
Françoise Gisou van der Goot1, Patrick A. Sandoz1, Robin A. Denhardt-Eriksson2, Laurence Abrami1, Francisco Mesquita1*, Vassily Hatzimanikatis2*
1Global Health Institute, 2Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
The complex architecture of the endoplasmic reticulum (ER) comprises distinct dynamic features, many at the nanoscale, that enable the coexistence of the nuclear envelope, regions of dense sheets and a branched tubular network that spans the cytoplasm. A key player in the formation of ER sheets is cytoskeleton-linking membrane protein 63 (CLIMP-63). The mechanisms by which CLIMP-63 coordinates ER structure remain elusive. We will report on the impact of S-acylation, a reversible post-translational lipid modification, on CLIMP-63 cellular distribution and function. The combination of native mass-spectrometry, with kinetic analysis of acylation and deacylation, and data-driven mathematical modelling, allowed an in depth understanding of the CLIMP-63 life cycle. In the ER, it assembles into trimeric units. These occasionally exit the ER to reach the plasma membrane. However, the majority undergoes S-acylation by ZDHHC6 in the ER where they further assemble into highly stable super-complexes. Super-resolution microscopy and focused ion beam electron microscopy showed that CLIMP-63 acylation-deacylation controls the abundance and fenestration of ER sheets. Overall, this study uncovers a dynamic lipid post-translational regulation of ER architecture.