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https://www.readbyqxmd.com/read/29602512/emerging-roles-of-dhhc-mediated-protein-s-palmitoylation-in-physiological-and-pathophysiological-context
#1
REVIEW
Indranil De, Sushabhan Sadhukhan
Protein S-palmitoylation refers to a post-translational modification (PTM) wherein palmitic acid, a 16-carbon long saturated fatty acid gets covalently attached to Cys sidechain of a protein. It has been known to the literature for almost 50 years and in general, this PTM is believed to facilitate membrane attachments of proteins for the obvious hydrophobicity of the palmitoyl group. But after the discovery of the protein palmitoyl acyltransferases (PATs, also known as DHHC-PATs), a major paradigm shift has been observed in the field of protein S-palmitoylation...
March 22, 2018: European Journal of Cell Biology
https://www.readbyqxmd.com/read/29429998/zdhhc11-modulates-innate-immune-response-to-dna-virus-by-mediating-mita-irf3-association
#2
Ying Liu, Qian Zhou, Li Zhong, Heng Lin, Ming-Ming Hu, Yan Zhou, Hong-Bing Shu, Shu Li
MITA is a central adaptor in innate immune responses to DNA viruses. The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic. Here we identified ZDHHC11, a member of DHHC palmitoyl transferase family, as a positive regulator of DNA virus-triggered signaling. Overexpression of ZDHHC11 activated the IFN-β promoter, while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes. Zdhhc11-/- mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection...
February 12, 2018: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/29326245/fatty-acyl-recognition-and-transfer-by-an-integral-membrane-s-acyltransferase
#3
Mitra S Rana, Pramod Kumar, Chul-Jin Lee, Raffaello Verardi, Kanagalaghatta R Rajashankar, Anirban Banerjee
DHHC (Asp-His-His-Cys) palmitoyltransferases are eukaryotic integral membrane enzymes that catalyze protein palmitoylation, which is important in a range of physiological processes, including small guanosine triphosphatase (GTPase) signaling, cell adhesion, and neuronal receptor scaffolding. We present crystal structures of two DHHC palmitoyltransferases and a covalent intermediate mimic. The active site resides at the membrane-cytosol interface, which allows the enzyme to catalyze thioester-exchange chemistry by using fatty acyl-coenzyme A and explains why membrane-proximal cysteines are candidates for palmitoylation...
January 12, 2018: Science
https://www.readbyqxmd.com/read/29287726/ccn3-secretion-is-regulated-by-palmitoylation-via-zdhhc22
#4
Yujin Kim, Hayoung Yang, Jeong-Ki Min, Young-Jun Park, Seung Hun Jeong, Sung-Wuk Jang, Sungbo Shim
Normal extracellular secretion of nephroblastoma overexpressed (NOV, also known as CCN3) is important for the adhesion, migration, and differentiation of cells. In previous studies, we have shown that the intracellular accumulation of CCN3 inhibits the growth of prominent neurons. Increased intracellular CCN3 can be induced through various processes, such as transcription, detoxification, and posttranslational modification. In general, posttranslational modifications are very important for protein secretion...
January 22, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29286308/selenoprotein-k-increases-efficiency-of-dhhc6-catalyzed-protein-palmitoylation-by-stabilizing-the-acyl-dhhc6-intermediate
#5
Gregory J Fredericks, FuKun W Hoffmann, Robert J Hondal, Sharon Rozovsky, Johann Urschitz, Peter R Hoffmann
Selenoprotein K (SELENOK) is a selenocysteine (Sec)-containing protein localized in the endoplasmic reticulum (ER) membrane where it interacts with the DHHC6 (where single letter symbols represent Asp-His-His-Cys amino acids) enzyme to promote protein acyl transferase (PAT) reactions. PAT reactions involve the DHHC enzymatic capture of palmitate via a thioester bond to cysteine (Cys) residues that form an unstable palmitoyl-DHHC intermediate, followed by transfer of palmitate to Cys residues of target proteins...
December 29, 2017: Antioxidants (Basel, Switzerland)
https://www.readbyqxmd.com/read/29187538/the-absence-of-dhhc3-affects-primary-and-latent-herpes-simplex-virus-1-infection
#6
Shaohui Wang, Kevin R Mott, Marianne Cilluffo, Casey L Kilpatrick, Shoko Murakami, Alexander V Ljubimov, Konstantin G Kousoulas, Sita Awasthi, Bernhard Luscher, Homayon Ghiasi
UL20, an essential herpes simplex virus 1 (HSV-1) protein, is involved in cytoplasmic envelopment of virions and virus egress. We reported recently that UL20 can bind to a host protein encoded by the zinc finger DHHC-type containing 3 ( ZDHHC3 ) gene (also known as Golgi-specific DHHC zinc finger protein [GODZ]). Here, we show for the first time that HSV-1 replication is compromised in murine embryonic fibroblasts (MEFs) isolated from GODZ-/- mice. The absence of GODZ resulted in blocking palmitoylation of UL20 and altered localization and expression of UL20 and glycoprotein K (gK); the expression of gB and gC; and the localization and expression of tegument and capsid proteins within HSV-1-infected MEFs...
February 15, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29079573/the-palmitoyltransferase-zdhhc20-enhances-interferon-induced-transmembrane-protein-3-ifitm3-palmitoylation-and-antiviral-activity
#7
Temet M McMichael, Lizhi Zhang, Mahesh Chemudupati, Jocelyn C Hach, Adam D Kenney, Howard C Hang, Jacob S Yount
Interferon-induced transmembrane protein 3 (IFITM3) is a cellular endosome- and lysosome-localized protein that restricts numerous virus infections. IFITM3 is activated by palmitoylation, a lipid posttranslational modification. Palmitoylation of proteins is primarily mediated by zinc finger DHHC domain-containing palmitoyltransferases (ZDHHCs), but which members of this enzyme family can modify IFITM3 is not known. Here, we screened a library of human cell lines individually lacking ZDHHCs 1-24 and found that IFITM3 palmitoylation and its inhibition of influenza virus infection remained strong in the absence of any single ZDHHC, suggesting functional redundancy of these enzymes in the IFITM3-mediated antiviral response...
December 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29055014/protein-acyltransferase-dhhc3-regulates-breast-tumor-growth-oxidative-stress-and-senescence
#8
Chandan Sharma, Hong-Xing Wang, Qinglin Li, Konstantin Knoblich, Emily S Reisenbichler, Andrea L Richardson, Martin E Hemler
DHHC-type protein acyltransferases may regulate the localization, stability, and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3 -ablated cells...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/29046345/endoplasmic-reticulum-transmembrane-proteins-zdhhc1-and-sting-both-act-as-direct-adaptors-for-irf3-activation-in-teleost
#9
Xiaowen Xu, Meifeng Li, Zhen Wu, Haizhou Wang, Liqiang Wang, Keyi Huang, Xiancheng Liu, Qunhao Hou, Gang Lin, Chengyu Hu
IFN regulatory factor (IRF)3 is a central regulator for IFN-β expression in different types of pathogenic infections. Mammals have various pathogenic sensors that are involved in monitoring pathogen intrusions. These sensors can trigger IRF3-mediated antiviral responses through different pathways. Endoplasmic reticulum-associated proteins stimulator of IFN gene (STING) and zinc finger DHHC-type containing 1 (ZDHHC1) are critical mediators of IRF3 activation in response to viral DNA infections. In this study, grass carp STING and ZDHHC1 were found to have some similar molecular features and subcellular localization, and both were upregulated upon stimulation with polyinosinic:polycytidylic acid, B-DNA, or Z-DNA...
November 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29038583/zdhhc13-dependent-drp1-s-palmitoylation-impacts-brain-bioenergetics-anxiety-coordination-and-motor-skills
#10
Eleonora Napoli, Gyu Song, Siming Liu, Alexsandra Espejo, Carlos J Perez, Fernando Benavides, Cecilia Giulivi
Protein S-palmitoylation is a reversible post-translational modification mediated by palmitoyl acyltransferase enzymes, a group of Zn2+ -finger DHHC-domain-containing proteins (ZDHHC). Here, for the first time, we show that Zdhhc13 plays a key role in anxiety-related behaviors and motor function, as well as brain bioenergetics, in a mouse model (luc) carrying a spontaneous Zdhhc13 recessive mutation. At 3 m of age, mutant mice displayed increased sensorimotor gating, anxiety, hypoactivity, and decreased motor coordination, compared to littermate controls...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28962849/the-expression-of-select-genes-necessary-for-membrane-associated-estrogen-receptor-signaling-differ-by-sex-in-adult-rat-hippocampus
#11
John Meitzen, Kyla A Britson, Krista Tuomela, Paul G Mermelstein
17β-estradiol can rapidly modulate neuron function via membrane estrogen receptors (ERs) in a sex-specific manner. For example, female rat hippocampal neurons express palmitoylated versions of ERα and ERβ that associate with the plasma membrane. These membrane-associated ERs are organized by caveolin proteins into functional signaling microdomains with metabotropic glutamate receptors (mGluRs). ER/mGluR signaling mediates several sex-specific estradiol actions on hippocampal neuron function. An important unanswered question regards the mechanism by which sex-specific membrane-associated ER signaling is generated, especially since it has been previously demonstrated that mGluR action is not sex-specific...
September 28, 2017: Steroids
https://www.readbyqxmd.com/read/28826475/identification-and-dynamics-of-the-human-zdhhc16-zdhhc6-palmitoylation-cascade
#12
Laurence Abrami, Tiziano Dallavilla, Patrick A Sandoz, Mustafa Demir, Béatrice Kunz, Georgios Savoglidis, Vassily Hatzimanikatis, F Gisou van der Goot
S-Palmitoylation is the only reversible post-translational lipid modification. Knowledge about the DHHC palmitoyltransferase family is still limited. Here we show that human ZDHHC6, which modifies key proteins of the endoplasmic reticulum, is controlled by an upstream palmitoyltransferase, ZDHHC16, revealing the first palmitoylation cascade. The combination of site specific mutagenesis of the three ZDHHC6 palmitoylation sites, experimental determination of kinetic parameters and data-driven mathematical modelling allowed us to obtain detailed information on the eight differentially palmitoylated ZDHHC6 species...
August 15, 2017: ELife
https://www.readbyqxmd.com/read/28757145/structural-basis-for-substrate-recognition-by-the-ankyrin-repeat-domain-of-human-dhhc17-palmitoyltransferase
#13
Raffaello Verardi, Jin-Sik Kim, Rodolfo Ghirlando, Anirban Banerjee
DHHC enzymes catalyze palmitoylation, a major post-translational modification that regulates a number of key cellular processes. There are up to 24 DHHCs in mammals and hundreds of substrate proteins that get palmitoylated. However, how DHHC enzymes engage with their substrates is still poorly understood. There is currently no structural information about the interaction between any DHHC enzyme and protein substrates. In this study we have investigated the structural and thermodynamic bases of interaction between the ankyrin repeat domain of human DHHC17 (ANK17) and Snap25b...
September 5, 2017: Structure
https://www.readbyqxmd.com/read/28734079/post-translational-palmitoylation-controls-the-voltage-gating-and-lipid-raft-association-of-the-calhm1-channel
#14
Akiyuki Taruno, Hongxin Sun, Koichi Nakajo, Tatsuro Murakami, Yasuyoshi Ohsaki, Mizuho A Kido, Fumihito Ono, Yoshinori Marunaka
KEY POINTS: Calcium homeostasis modulator 1 (CALHM1), a new voltage-gated ATP- and Ca(2+) -permeable channel, plays important physiological roles in taste perception and memory formation. Regulatory mechanisms of CALHM1 remain unexplored, although the biophysical disparity between CALHM1 gating in vivo and in vitro suggests that there are undiscovered regulatory mechanisms. Here we report that CALHM1 gating and association with lipid microdomains are post-translationally regulated through the process of protein S-palmitoylation, a reversible attachment of palmitate to cysteine residues...
September 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28724772/binding-of-herpes-simplex-virus-1-ul20-to-godz-dhhc3-affects-its-palmitoylation-and-is-essential-for-infectivity-and-proper-targeting-and-localization-of-ul20-and-glycoprotein-k
#15
Shaohui Wang, Kevin R Mott, Kolja Wawrowsky, Konstantin G Kousoulas, Bernhard Luscher, Homayon Ghiasi
Herpes simplex virus 1 (HSV-1) UL20 plays a crucial role in the envelopment of the cytoplasmic virion and its egress. It is a nonglycosylated envelope protein that is regulated as a γ1 gene. Two-hybrid and pulldown assays demonstrated that UL20, but no other HSV-1 gene-encoded proteins, binds specifically to GODZ (also known as DHHC3), a cellular Golgi apparatus-specific Asp-His-His-Cys (DHHC) zinc finger protein. A catalytically inactive dominant-negative GODZ construct significantly reduced HSV-1 replication in vitro and affected the localization of UL20 and glycoprotein K (gK) and their interactions but not glycoprotein C (gC)...
October 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28630137/structure-and-function-of-dhhc-protein-s-acyltransferases
#16
REVIEW
Colin D Gottlieb, Maurine E Linder
It has been estimated that 10% of the human genome encodes proteins that are fatty acylated at cysteine residues. The vast majority of these proteins are modified by members of the DHHC protein family, which carry out their enzymatic function on the cytoplasmic face of cell membranes. The biomedical importance of DHHC proteins is underscored by their association with human disease; unique and essential roles for DHHC proteins have been uncovered using DHHC-deficient mouse models. Accordingly, there is great interest in elucidating the molecular mechanisms that underlie DHHC protein function...
August 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28167757/molecular-basis-of-fatty-acid-selectivity-in-the-zdhhc-family-of-s-acyltransferases-revealed-by-click-chemistry
#17
Jennifer Greaves, Kevin R Munro, Stuart C Davidson, Matthieu Riviere, Justyna Wojno, Terry K Smith, Nicholas C O Tomkinson, Luke H Chamberlain
S-acylation is a major posttranslational modification, catalyzed by the zinc finger DHHC domain containing (zDHHC) enzyme family. S-acylated proteins can be modified by different fatty acids; however, very little is known about how zDHHC enzymes contribute to acyl chain heterogeneity. Here, we used fatty acid-azide/alkyne labeling of mammalian cells, showing their transformation into acyl-CoAs and subsequent click chemistry-based detection, to demonstrate that zDHHC enzymes have marked differences in their fatty acid selectivity...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28154191/specific-palmitoyltransferases-associate-with-and-activate-the-epithelial-sodium-channel
#18
Anindit Mukherjee, Zhijian Wang, Carol L Kinlough, Paul A Poland, Allison L Marciszyn, Nicolas Montalbetti, Marcelo D Carattino, Michael B Butterworth, Thomas R Kleyman, Rebecca P Hughey
The epithelial sodium channel (ENaC) has an important role in regulating extracellular fluid volume and blood pressure, as well as airway surface liquid volume and mucociliary clearance. ENaC is a trimer of three homologous subunits (α, β, and γ). We previously reported that cytoplasmic residues on the β (βCys-43 and βCys-557) and γ (γCys-33 and γCys-41) subunits are palmitoylated. Mutation of Cys that blocked ENaC palmitoylation also reduced channel open probability. Furthermore, γ subunit palmitoylation had a dominant role over β subunit palmitoylation in regulating ENaC...
March 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28057756/dhhc7-palmitoylates-glucose-transporter-4-glut4-and-regulates-glut4-membrane-translocation
#19
Keyong Du, Shoko Murakami, Yingmin Sun, Casey L Kilpatrick, Bernhard Luscher
Insulin-dependent translocation of glucose transporter 4 (Glut4) to the plasma membrane plays a key role in the dynamic regulation of glucose homeostasis. We recently showed that this process is critically dependent on palmitoylation of Glut4 at Cys-223. To gain further insights into the regulation of Glut4 palmitoylation, we set out to identify the palmitoyl acyltransferase (PAT) involved. Here we report that among 23 mammalian DHHC proteins, DHHC7 is the major Glut4 PAT, based on evidence that ectopic expression of DHHC7 increased Glut4 palmitoylation, whereas DHHC7 knockdown in 3T3-L1 adipocytes and DHHC7 KO in adipose tissue and muscle decreased Glut4 palmitoylation...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28031421/the-palmitoyltransferase-approximated-promotes-growth-via-the-hippo-pathway-by-palmitoylation-of-fat
#20
Hitoshi Matakatsu, Seth S Blair, Richard G Fehon
The large protocadherin Fat functions to promote Hippo pathway activity in restricting tissue growth. Loss of Fat leads to accumulation of the atypical myosin Dachs at the apical junctional region, which in turn promotes growth by inhibiting Warts. We previously identified Approximated (App), a DHHC domain palmitoyltransferase, as a negative regulator of Fat signaling in growth control. We show here that App promotes growth by palmitoylating the intracellular domain of Fat, and that palmitoylation negatively regulates Fat function...
January 2, 2017: Journal of Cell Biology
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