Lipid-induced S-palmitoylation as a Vital Regulator of Cell Signaling and Disease Development

Abstract

Lipid metabolites are emerging as pivotal regulators of protein function and cell signaling. The availability of intracellular fatty acid is tightly regulated by glycolipid metabolism and may affect human body through many biological mechanisms. Recent studies have demonstrated palmitate, either from exogenous fatty acid uptake or de novo fatty acid synthesis, may serve as the substrate for protein palmitoylation and regulate protein function via palmitoylation. Palmitoylation, the most-studied protein lipidation, encompasses the reversible covalent attachment of palmitate moieties to protein cysteine residues. It controls various cellular physiological processes and alters protein stability, conformation, localization, membrane association and interaction with other effectors. Dysregulation of palmitoylation has been implicated in a plethora of diseases, such as metabolic syndrome, cancers, neurological disorders and infections. Accordingly, it could be one of the molecular mechanisms underlying the impact of palmitate metabolite on cellular homeostasis and human diseases. Herein, we explore the relationship between lipid metabolites and the regulation of protein function through palmitoylation. We review the current progress made on the putative role of palmitate in altering the palmitoylation of key proteins and thus contributing to the pathogenesis of various diseases, among which we focus on metabolic disorders, cancers, inflammation and infections, neurodegenerative diseases. We also highlight the opportunities and new therapeutics to target palmitoylation in disease development.

Keywords: Cancer; Inflammation; Lipid metabolism; Neurodegeneration; Palmitoylation.

Figure 1

The Dynamic Regulation of Protein S-Palmitoylation. Palmitoyl acyltransferases perform the autopalmitoylation within the ZDHHC domain and then transfer palmitate to the substrate protein cysteines to accomplish palmitoylation. The depalmitoylation is catalyzed by thioesterases (APTs and ABHDs) which remove the palmitate from the proteins. PPTs are mainly localized in lysosome. Some proteins can be autopalmitoylation non-enzymatically. The lipid bilayers represent endoplasmic reticulum (ER), Golgi lumen and plasma membrane (PM).

Figure 2

The link between lipid metabolism and S-palmitoylation. Glucose transporter (GLUT4) transports glucose into cell while CD36 mediates the uptake and endocytosis of exogenous free fatty acids (FFAs). Acetyl-CoA is generated from citrate by ATP-citrate lyase (ACLY); and then, Acetyl-CoA is carboxylated to malonyl-CoA by Acetyl-CoA carboxylase (ACC). Fatty acid synthase (FASN) is the key rate-limiting enzyme that catalyzes the synthesis of palmitate from Acetyl-CoA and malonyl-CoA (the byproducts of glucose metabolism and Krebs cycle). Long-chain Acyl-CoA syntheses (ACSL) catalyzes FAs into Acyl-CoAs, e.g. Palmitoyl-CoA, which is the substrate for palmitoylation.

Figure 3

Schematic examples of protein palmitoylation and metabolism, cancer, inflammation, neurodegeneration. a. In the model of non-alcoholic steatohepatitis (NASH), palmitate induces CD36 palmitoylation, and the enhanced palmitoylation promotes the CD36/Lyn/Fyn complex, impairs FA β-oxidation, causes lipid accumulation, increases inflammation and cytokines release. b. Transcriptional enhanced associate domain (TEAD) is autopalmitoylated and it could be affected by intracellular palmitate levels. Palmitoylation of TEAD is required for its association with YAP and the regulation of transcriptional output of Hippo signaling. c. The de novo synthesis of palmitate by FASN and CD36-mediated exogenous FA uptake are two important sources for MYD88palmitoylation, which is essential for IRAK4 recruitment, p38MAPK and p65 activation, TLR4/MYD88 pathway. d. Palmitate deposition in the hippocampus increases GluA1 palmitoylation through FoxO3a-mediated overexpression of zDHHC3, resulting in altered GluA1 localization and function, suppressed AMPAR response and impairment of cognitive function. Figures include data from references , , , .