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Review
. 2018 Jul 19;25(7):817-831.
doi: 10.1016/j.chembiol.2018.05.003. Epub 2018 May 31.

Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities

Baoen Chen  1 , Yang Sun  1 , Jixiao Niu  1 , Gopala K Jarugumilli  1 , Xu Wu  2
Affiliations
Review

Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities

Baoen Chen et al. Cell Chem Biol. .

Abstract

Protein lipidation is an important co- or posttranslational modification in which lipid moieties are covalently attached to proteins. Lipidation markedly increases the hydrophobicity of proteins, resulting in changes to their conformation, stability, membrane association, localization, trafficking, and binding affinity to their co-factors. Various lipids and lipid metabolites serve as protein lipidation moieties. The intracellular concentrations of these lipids and their derivatives are tightly regulated by cellular metabolism. Therefore, protein lipidation links the output of cellular metabolism to the regulation of protein function. Importantly, deregulation of protein lipidation has been linked to various diseases, including neurological disorders, metabolic diseases, and cancers. In this review, we highlight recent progress in our understanding of protein lipidation, in particular, S-palmitoylation and lysine fatty acylation, and we describe the importance of these modifications for protein regulation, cell signaling, and diseases. We further highlight opportunities and new strategies for targeting protein lipidation for therapeutic applications.

Keywords: bioorthogonal chemical reporters; cancer; drug discovery; fatty acylation; infectious diseases; palmitoylation; protein lipidation; signal transduction.

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Conflict of interest statement

Competing Financial Interests

Authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Protein lipidation links lipid metabolism to the regulation of protein functions
Proteins can be modified by at least 6 types of lipid, including saturated and unsaturated fatty acids (palmitate, myristate, and palmitoleate etc.), isoprenoids (farnesyl and geranylgeranyl), GPI anchors, cholesterols, phospholipids (not shown here) and lipid-derived electrophiles (HNE etc.). Cellular lipid metabolism affects the availability of fatty acyl-CoA and other lipid derivatives, which are used as substrates for protein lipidation. The 16-carbon fatty acid, palmitate, is a critical intermediate for the biosynthesis of other lipids in the cells. (FFA: free fatty acid; HNE: 4-hydroxynonenal; GPI: glycosylphosphatidylinositol; FPP: farnesyl pyrophosphate; GGPP: geranylgeranyl pyrophosphate; TCA cycle: tricarboxylic acid cycle or Krebs cycle).
Figure 2
Figure 2. Chemical and biochemical methods to detect protein lipidation
(A). Detection of S-acylated proteins by acyl exchange methods. (B). Detection of protein lipidation using bioorthogonal chemical reporters.
Figure 3
Figure 3. The dynamic regulation of protein S-palmitoylation
Palmitoyl acyltransferases (ZDHHC family enzymes, LPCAT) or autopalmitoylation are involved in adding palmitate to the Cys residue of proteins. The thioesterases or lipases (APTs and ABHDs) could remove the lipid chain from the proteins.
Figure 4
Figure 4. Function and regulation of TEAD autopalmitoylation
The Hippo pathway transcription factor TEAD is autopalmitoylated. Autopalmitoylation of TEAD may be regulated by intracellular concentration of palmitoyl-CoA, which is controlled by fatty acid metabolism. Palmitoylation of TEAD is required for its association with YAP and the regulation of transcriptional output of Hippo signaling.
See this image and copyright information in PMC

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