-
Signal Transduction and Targeted Therapy Dec 2022Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With... (Review)
Review
Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein-protein interactions and protein-DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.
Topics: Acyltransferases; Acylation; Proteins; Protein Processing, Post-Translational
PubMed: 36577755
DOI: 10.1038/s41392-022-01245-y -
Nature Jul 2022Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt...
Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling. Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the lumenal side, and the palmitoleoyl-CoA accesses the enzyme from the cytosolic side. The catalytic histidine triggers the transfer of the unsaturated palmitoleoyl group to the target serine on the Wnt hairpin 2, facilitated by the proximity of the two substrates. The inhibitor-bound structure shows that LGK974 occupies the palmitoleoyl-CoA binding site to prevent the reaction. Thus, this work provides a mechanism for Wnt acylation and advances the development of PORCN inhibitors for cancer treatment.
Topics: Acylation; Acyltransferases; Antineoplastic Agents; Binding Sites; Coenzyme A; Cryoelectron Microscopy; Histidine; Humans; Membrane Proteins; Neoplasms; Palmitoyl Coenzyme A; Pyrazines; Pyridines; Serine; Substrate Specificity; Wnt Signaling Pathway; Wnt3A Protein
PubMed: 35831507
DOI: 10.1038/s41586-022-04952-2 -
Nature Sep 2023Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the...
Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2). In other organisms, this activity is complemented by additional enzymes, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
Topics: Animals; Humans; Mice; Acyltransferases; Coenzyme A; Diacylglycerol O-Acyltransferase; Escherichia coli; Homeostasis; Triglycerides; Energy Metabolism; Nutrients; Fatty Acids
PubMed: 37648867
DOI: 10.1038/s41586-023-06497-4 -
Nature Sep 2019Signal transducer and activator of transcription 3 (STAT3) has a critical role in regulating cell fate, inflammation and immunity. Cytokines and growth factors activate...
Signal transducer and activator of transcription 3 (STAT3) has a critical role in regulating cell fate, inflammation and immunity. Cytokines and growth factors activate STAT3 through kinase-mediated tyrosine phosphorylation and dimerization. It remains unknown whether other factors promote STAT3 activation through different mechanisms. Here we show that STAT3 is post-translationally S-palmitoylated at the SRC homology 2 (SH2) domain, which promotes the dimerization and transcriptional activation of STAT3. Fatty acids can directly activate STAT3 by enhancing its palmitoylation, in synergy with cytokine stimulation. We further identified ZDHHC19 as a palmitoyl acyltransferase that regulates STAT3. Cytokine stimulation increases STAT3 palmitoylation by promoting the association between ZDHHC19 and STAT3, which is mediated by the SH3 domain of GRB2. Silencing ZDHHC19 blocks STAT3 palmitoylation and dimerization, and impairs the cytokine- and fatty-acid-induced activation of STAT3. ZDHHC19 is frequently amplified in multiple human cancers, including in 39% of lung squamous cell carcinomas. High levels of ZDHHC19 correlate with high levels of nuclear STAT3 in patient samples. In addition, knockout of ZDHHC19 in lung squamous cell carcinoma cells significantly blocks STAT3 activity, and inhibits the fatty-acid-induced formation of tumour spheres as well as tumorigenesis induced by high-fat diets in an in vivo mouse model. Our studies reveal that fatty-acid- and ZDHHC19-mediated palmitoylation are signals that regulate STAT3, which provides evidence linking the deregulation of palmitoylation to inflammation and cancer.
Topics: Acyltransferases; Animals; Carcinogenesis; Carcinoma, Squamous Cell; Conserved Sequence; Cysteine; Disease Models, Animal; Fatty Acids; Heterografts; Humans; Inflammation; Interferon-gamma; Interleukin-6; Lipoylation; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Transplantation; Phosphorylation; Protein Multimerization; STAT3 Transcription Factor; Signal Transduction; src Homology Domains
PubMed: 31462771
DOI: 10.1038/s41586-019-1511-x -
Nature Jun 2022Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals. A subfamily, palmitic acid esters...
Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80-90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.
Topics: Acyltransferases; Adipose Tissue; Animals; Diglycerides; Esterification; Esters; Fatty Acids; Humans; Hydroxy Acids; Insulin Resistance; Mice; Triglycerides
PubMed: 35676490
DOI: 10.1038/s41586-022-04787-x -
Current Opinion in Chemical Biology Dec 2021Protein S-acylation is a prevalent post-translational protein lipidation that is dynamically regulated by 'writer' protein S-acyltransferases and 'eraser' acylprotein... (Review)
Review
Protein S-acylation is a prevalent post-translational protein lipidation that is dynamically regulated by 'writer' protein S-acyltransferases and 'eraser' acylprotein thioesterases. The protein S-acyltransferases comprise 23 aspartate-histidine-histidine-cysteine (DHHC)-containing proteins, which transfer fatty acid acyl groups from acyl-coenzyme A onto protein substrates. DHHC proteins are increasingly recognized as critical regulators of S-acylation-mediated cellular processes and pathology. As our understanding of the importance and breadth of DHHC-mediated biology and pathology expands, so too does the need for chemical inhibitors of this class of proteins. In this review, we discuss the challenges and progress in DHHC inhibitor development, focusing on 2-bromopalmitate, the most commonly used inhibitor in the field, and N-cyanomethyl-N-myracrylamide, a new broad-spectrum DHHC inhibitor. We believe that current and ongoing advances in structure elucidation, mechanistic interrogation, and novel inhibitor design around DHHC proteins will spark innovative strategies to modulate these critical proteins in living systems.
Topics: Acylation; Acyltransferases; Cysteine; Lipoylation; Protein Processing, Post-Translational
PubMed: 34467875
DOI: 10.1016/j.cbpa.2021.07.002 -
The FEBS Journal Dec 2021Protein palmitoylation (S-acylation) has emerged as an important player in a range of cellular processes, and as a result, the palmitoyl-acyltransferase (PAT) enzymes... (Review)
Review
Protein palmitoylation (S-acylation) has emerged as an important player in a range of cellular processes, and as a result, the palmitoyl-acyltransferase (PAT) enzymes which mediate this modification have entered into the spotlight. Palmitoyltransferase ZDHHC5 (ZDHHC5) is among the more unique members of the PAT family as it is mainly localised to the plasma membrane and contains an extended cytoplasmic domain with several regulatory features. ZDHHC5 plays a vital role in a wide range of processes in different cell types. In this review, we offer a summary of the functions of ZDHHC5 in synaptic plasticity, cardiac function, cell adhesion and fatty acid uptake, among other processes. We also explore recent work has revealed several mechanisms to control the activity, localisation and function of ZDHHC5.
Topics: Acylation; Acyltransferases; Animals; Brain; Cell Membrane; Humans; Membrane Proteins; Neuronal Plasticity; Palmitic Acid; Protein Processing, Post-Translational
PubMed: 33415776
DOI: 10.1111/febs.15709 -
Nature Communications Oct 2023We report on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria, a classical one wherein the acylation of the sn-1 position of...
We report on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria, a classical one wherein the acylation of the sn-1 position of glycerol-3-phosphate (G3P) precedes that of sn-2 and another wherein acylations proceed in the reverse order. Two unique acyltransferases, PlsM and PlsB2, participate in both pathways and hold the key to the unusual positional distribution of acyl chains typifying mycobacterial glycerolipids wherein unsaturated substituents principally esterify position sn-1 and palmitoyl principally occupies position sn-2. While PlsM selectively transfers a palmitoyl chain to the sn-2 position of G3P and sn-1-lysophosphatidic acid (LPA), PlsB2 preferentially transfers a stearoyl or oleoyl chain to the sn-1 position of G3P and an oleyl chain to sn-2-LPA. PlsM is the first example of an sn-2 G3P acyltransferase outside the plant kingdom and PlsB2 the first example of a 2-acyl-G3P acyltransferase. Both enzymes are unique in their ability to catalyze acyl transfer to both G3P and LPA.
Topics: Acyltransferases; Glycerol-3-Phosphate O-Acyltransferase; Acylation; Mycobacterium
PubMed: 37872138
DOI: 10.1038/s41467-023-42478-x -
Journal of Inherited Metabolic Disease Jan 2022Mutation of the gene Tafazzin (TAZ) causes Barth syndrome, an X-linked disorder characterized by cardiomyopathy, skeletal muscle weakness, and neutropenia. TAZ is an... (Review)
Review
Mutation of the gene Tafazzin (TAZ) causes Barth syndrome, an X-linked disorder characterized by cardiomyopathy, skeletal muscle weakness, and neutropenia. TAZ is an acyltransferase that catalyzes the remodeling of cardiolipin, the signature phospholipid of the inner mitochondrial membrane. Here, we review the major model systems that have been established to study the role of cardiolipin remodeling in mitochondrial function and the pathogenesis of Barth syndrome. We summarize key features of each model and provide examples of how each has contributed to advance our understanding of TAZ function and Barth syndrome pathophysiology.
Topics: Acyltransferases; Animals; Barth Syndrome; Cardiolipins; Disease Models, Animal; Gene Knockout Techniques; Humans; Mitochondria; Mitochondrial Membranes; Mutation
PubMed: 34370877
DOI: 10.1002/jimd.12423 -
Science China. Life Sciences Mar 2016Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate... (Review)
Review
Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.
Topics: Acyltransferases; Animals; Eating; Energy Metabolism; Gene Deletion; Gene Expression Regulation, Enzymologic; Ghrelin; Humans; Obesity; Tissue Distribution
PubMed: 26732975
DOI: 10.1007/s11427-015-4973-6