The zDHHC family of S-acyltransferases

Chikungunya virus (CHIKV) is transmitted to people by mosquitoes, and CHIKV infection causes fever and joint pain. Fatty acid synthase (FASN) has been identified as a proviral factor for CHIKV. How FASN participates in CHIKV replication remains to be elucidated. In this study, we demonstrated that palmitic acid (PA) can restore the suppression of CHIKV replication by FASN inhibitors. The palmitoylation and plasma membrane localization of CHIKV nsP1 were reduced by FASN inhibitors. Triple mutation of Cys417, Cys418, and Cys419 in nsP1 blocked its palmitoylation and severely disrupted CHIKV replication. Furthermore, two zinc finger DHHC domaincontaining palmitoyltransferases (ZDHHCs), ZDHHC2 and ZDHHC19, promoted nsP1 palmitoylation and CHIKV replication. Our results not only identified the key enzymes for the palmitoylation of nsP1 but also provided mechanistic insights into the roles of FASN in CHIKV replication. IMPORTANCE S-palmitoylation is an important form of lipid posttranslational modification, which affects the function of proteins by regulating their transport, stability, and localization. Previous studies have shown that FASN is critical for CHIKV replication; however, the mechanism for this function of FASN remains unknown. The key zinc finger DHHC domain-containing palmitoyltransferases involved in the palmitoylation of nsP1 are not clear. We demonstrated that FASN promoted CHIKV replication through nsP1 palmitoylation. ZDHHC2 and ZDHHC19 were identified as the major enzymes for nsP1 palmitoylation. Since nsP1 proteins are conserved in alphaviruses, our results highlight the mechanisms by which alphavirus nsP1 is palmitoylated.

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“…Protein palmitoylation is mediated by PATs and protein thioesterases (16). In our study, ZDHHC2 and ZDHHC19 are the major PATs for nsP1.…”

Section: Discussionmentioning

confidence: 57%

“…ZDHHC2 and ZDHHC19 promote the palmitoylation of nsP1. Protein palmitoylation is mediated mainly by ZDHHCs (16). Next, we screened for ZDHHCs associated with nsP1.…”

Section: Resultsmentioning

confidence: 99%

Fatty Acid Synthase Promotes the Palmitoylation of Chikungunya Virus nsP1

Zhang

Zhao

Zhang

2019

J Virol

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“…15 Subsequently, 24 PATs were identified in human and designated ZDHHC1 to 24 (without ZDHHC10 and including ZDHHC11B). 16 Palmitoylation proceeds via a two-step catalytic mechanism. In the first step, the cysteine residue in the DHHC motif is acylated with palmitate from palmitoyl-CoA (this step is often referred to as auto-palmitoylation, as APTs incubated with palmitoyl-CoA are spontaneously palmitoylated).…”

Section: Introductionmentioning

confidence: 99%

Palmitoylation: a protein S-acylation with implications for breast cancer

Anderson

Ragan

2016

npj Breast Cancer

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Protein S-acylation is a reversible post-translational lipid modification that involves linkage of a fatty acid chain predominantly to a cysteine amino acid via a thioester bond. The fatty acid molecule is primarily palmitate, thus the term ‘palmitoylation’ is more commonly used. Palmitoylation has been found to modulate all stages of protein function including maturational processing, trafficking, membrane anchoring, signaling range and efficacy, and degradation. In breast cancer, palmitoylation has been shown to control the function of commonly dysregulated genes including estrogen receptors, the epidermal growth factor (EGF) family of receptors, and cancer stem cell markers. Importantly, palmitoylation is a critical factor controlling the formation of complexes at the plasma membrane involving tetraspanins, integrins, and gene products that are key to cell–cell communication. During metastasis, cancer cells enhance their metastatic capacity by interacting with stroma and immune cells. Although aberrant palmitoylation could contribute to tumor initiation and growth, its potential role in these cell–cell interactions is of particular interest, as it may provide mechanistic insight into metastasis, including cancer cell-driven immune modulation. Compelling evidence for a role for aberrant palmitoylation in breast cancer remains to be established. To this end, in this review we summarize emerging evidence and highlight pertinent knowledge gaps, suggesting directions for future research.

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“…22,24,28,29 DHHC proteins can cycle between different compartments, as was shown for DHHC2 which moves between the plasma membrane and endosomes. Special attention has to be paid to what co-localization markers are used for determining the protein disposition within the cell, particularly when considering closely positioned cellular compartments such as Golgi, trans-Golgi network (TGN), and recycling endosomes.…”

Section: Dhhc Proteins: Localizationmentioning

confidence: 99%

“…19 ANK domains have been shown to be involved in protein-protein interactions 21 and, in the case of DHHC enzymes, play a role in substrate recognition and interaction. 22 Additionally, other protein binding domains, such as SH3 (Src Homology 3) and PDZ (PSD95-Dlg-1-ZO) domains, have been identified in some of the DHHC proteins ( Figure 1). 23,24 The DHHC-CRD of PATs displays some homology with the C 2 H 2 zinc-finger and non-Cys 2 His 2 motif and has been termed NEW 1.…”

Section: Dhhc Proteins: Structurementioning

confidence: 99%

Protein palmitoylation: Palmitoyltransferases and their specificity

Tabaczar

Czogalla

Podkalicka

et al. 2017

Exp Biol Med (Maywood)

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Protein palmitoylation is one of most important reversible post-translational modifications of protein function in cellsignaling systems. This review gathers the latest information on the molecular mechanism of protein palmitoyl transferase action. It also discusses the issue of substrate specificity of palmitoyl transferases. Another important question is the role of depalmitoylation enzymes. This review should help to formulate questions concerning the regulation of activity of particular PATs as well as of depalmitoylating enzymes (APT). AbstractA plethora of novel information has emerged over the past decade regarding protein lipidation. The reversible attachment of palmitic acid to cysteine residues, termed S-palmitoylation, has focused a special attention. This is mainly due to the unique role of this modification in the regulation of protein trafficking and function. A large family of protein acyltransferases (PATs) containing a conserved aspartate-histidine-histidine-cysteine motif use ping-pong kinetic mechanism to catalyze S-palmitoylation of a substrate protein. Here, we discuss the topology of PAT proteins and their cellular localization. We will also give an overview of the mechanism of protein palmitoylation and how it is regulated. New information concerning the recent discovery of depalmitoylating enzymes belonging to the family of a/b-hydrolase domain-containing protein 17 (ABHD17A) is included. Considering the recent advances that have occurred in understanding the mechanisms underlying the interplay between palmitoylation and depalmitoylation, it is clear that we are beginning to understand the fundamental nature of how cellular signal-transduction mediates membrane-level organization in health and disease.

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The zDHHC family of S-acyltransferases

Cited by 63 publications

References 65 publications

Fatty Acid Synthase Promotes the Palmitoylation of Chikungunya Virus nsP1

Fatty Acid Synthase Promotes the Palmitoylation of Chikungunya Virus nsP1

Palmitoylation: a protein S-acylation with implications for breast cancer

Protein palmitoylation: Palmitoyltransferases and their specificity

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