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Mechanisms and functions of protein S-acylation

Nature Reviews Molecular Cell Biology (2024)Cite this article

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Abstract

Over the past two decades, protein S-acylation (often referred to as S-palmitoylation) has emerged as an important regulator of vital signalling pathways. S-Acylation is a reversible post-translational modification that involves the attachment of a fatty acid to a protein. Maintenance of the equilibrium between protein S-acylation and deacylation has demonstrated profound effects on various cellular processes, including innate immunity, inflammation, glucose metabolism and fat metabolism, as well as on brain and heart function. This Review provides an overview of current understanding of S-acylation and deacylation enzymes, their spatiotemporal regulation by sophisticated multilayered mechanisms, and their influence on protein function, cellular processes and physiological pathways. Furthermore, we examine how disruptions in protein S-acylation are associated with a broad spectrum of diseases from cancer to autoinflammatory disorders and neurological conditions.

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Fig. 1: S-Acylation enzymes and cycles.
Fig. 2: Consequences of protein S-acylation.
Fig. 3: S-Acylation and innate immunity.
Fig. 4: Effect of S-acylation on physiological pathways.

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Acknowledgements

The authors thank T. Kawate for creating original Fig. 1d and A. R. Wild for editorial assistance. F.G.v.d.G. and F.S.M. were supported by the Swiss National Science Foundation (SNSF-31CA30_196651, SNSF-310030_192608) and by Carigest SA. B.C.D. was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35 GM119840). S.X.B. is supported by the Canadian Institutes for Health Research Foundation Grant (FDN-159907).

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Authors and Affiliations

  1. Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Francisco S. Mesquita, Laurence Abrami & F. Gisou van der Goot

  2. Department of Molecular Medicine, Cornell University, Ithaca, NY, USA

    Maurine E. Linder

  3. Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    Shernaz X. Bamji

  4. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Bryan C. Dickinson

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BrainPalmSeq: https://brainpalmseq.med.ubc.ca/

CellPalmSeq: https://cellpalmseq.med.ubc.ca/

SwissPalm: https://swisspalm.org/

Supplementary information

Glossary

Acyl-CoA

(Acyl-coenzyme A). A group of coenzymes involved in fatty acid metabolism.

Dendritic spines

Small membrane protrusions that receive input from a single axon at the synapse; similar protrusions can also occur on flat membranes (dendritic shafts).

Fatty acids

Carboxylic acids with an aliphatic chain, which are either saturated or unsaturated. S-Acylation mostly adds saturated long-chain carboxylic (fatty) acids with aliphatic tails of 13–21 carbons (chemical formula CH3(CH2)nCOOH), but can also add unsaturated fatty acids such as arachidonic or oleic acids.

Hydrophobic mismatch

A situation where the length of an orthogonal transmembrane helix of a protein differs from (that is, is shorter or longer than) the thickness of a membrane.

Inflammasome

A multiprotein proteolytic complex that forms in the cytosol in response to sensing of molecules of bacterial origin or danger signals such as low potassium levels; inflammasomes cleave the precursors of IL-1β and gasdermins.

Insulin

A peptide hormone that regulates glucose homeostasis and has anabolic actions on target tissues that enable the body to build energy reserves when glucose is abundant.

Membrane contact sites

Sites of membrane juxtaposition between organelles.

mTOR

A kinase that regulates numerous cellular processes, including cell growth and proliferation, that are important in cancer.

Oligodendrocytes

Glial cells of the central nervous system whose main function is to insulate the axons of neurons by forming a myelin sheath.

Pyroptosis

A form of programmed cell death that occurs during inflammation and involves gasdermin pore formation in the cytoplasmic face of the plasma membrane.

Spike protein

The SARS-CoV-2 viral glycoprotein responsible for its characteristic crown appearance; the spike protein binds to host cells and facilitates fusion of the viral membrane with that of the infected cell.

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S. Mesquita, F., Abrami, L., Linder, M.E. et al. Mechanisms and functions of protein S-acylation. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00700-8

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