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Article
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HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription
The regulatory mechanism and functional consequence of lysine lactylation remain to be explored. Here, the authors identify HBO1 as a lysine lactyltransferase and suggest a potential role of HBO1 in tumorigenesis through H3K9la-mediated transcription regulation.
- Ziping Niu
- , Chen Chen
- & Kai Zhang
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Article
| Open Access
Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Most individuals with primary familial brain calcification (PFBC) remain genetically unsolved. Here the authors show that NAA60 biallelic variants cause PFBC, likely via reduced N-terminal acetylation and SLC20A2 levels with impaired phosphate uptake.
- Viorica Chelban
- , Henriette Aksnes
- & Henry Houlden
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Article
| Open Access
Microtubule damage shapes the acetylation gradient
Microtubules are acetylated on the inside of their hollow lumen, a modification linked to their lifespan. Here, the authors show that damage holes act as entry points for a deacetylase to access the lumen, thereby locally counteracting acetylation.
- Mireia Andreu-Carbó
- , Cornelia Egoldt
- & Charlotte Aumeier
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Article
| Open Access
DJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride
Human protein DJ-1 displays neuroprotective properties. Here, the authors demonstrate that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), thereby protecting proteins from acylation by this highly reactive metabolite spontaneously forming in glycolysis.
- Aizhan Akhmadi
- , Adilkhan Yeskendir
- & Darkhan Utepbergenov
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Article
| Open Access
Spatiotemporal and direct capturing global substrates of lysine-modifying enzymes in living cells
Here the authors report a strategy to directly capture substrates of lysine-modifying enzymes via post-translational modification (PTM)-acceptor residue crosslinking in living cells, enabling global profiling of substrates of PTM-enzymes and validation of PTM-sites in a straightforward manner.
- Hao Hu
- , Wei Hu
- & Xiao-Hua Chen
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Article
| Open Access
Acetylation is required for full activation of the NLRP3 inflammasome
The NLRP3 inflammasome is activated in two steps, priming and assembly, in response to endogenous, microbial, and other environmental danger signals. Here authors show that the assembly step is regulated by acetylation, and inhibition of this post-translational modification prevents full activation of the inflammasome.
- Yening Zhang
- , Ling Luo
- & Kai Zhao
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Article
| Open Access
Acetylation regulates the oligomerization state and activity of RNase J, the Helicobacter pylori major ribonuclease
Here the authors find that RNase J, the major ribonuclease of the gastric pathogen Helicobacter pylori is post-translationally modified by acetylation. They show that acetylation can control RNase J activity.
- Alejandro Tejada-Arranz
- , Aleksei Lulla
- & Hilde De Reuse
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Article
| Open Access
SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway
Interferon-gamma (IFN-γ) is an important but not exclusive proinflammatory mediator in macrophages. Here authors show that IFN-γ-independent macrophage autoactivation involves endoplasmic reticulum (ER) stress which in turn induces the GTP-binding protein Septin2 to limit inflammation via a negative feedback loop.
- Beibei Fu
- , Yan Xiong
- & Haibo Wu
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Article
| Open Access
N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.
- Sylvia Varland
- , Rui Duarte Silva
- & Thomas Arnesen
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Article
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Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction
How cellular metabolism is connected to differentiation remains poorly understood. Here the authors report a regulatory cascade in which circulating citrate regulates sperm production by controlling protein stability via a specific protein post-translational modification.
- Charlotte M. François
- , Thomas Pihl
- & Bruno Hudry
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Article
| Open Access
Acetylation-dependent coupling between G6PD activity and apoptotic signaling
Lysine acetylation is highly prevalent in metabolic enzymes. Here, the authors highlight the diverse roles of acetylation and show that G6PD acetylation can activate/deactivate G6PD, and promote G6PD ubiquitylation and phosphorylation, its interaction with p53, and p53-dependent pro-apoptotic events.
- Fang Wu
- , Natali H. Muskat
- & Eyal Arbely
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Article
| Open Access
SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity
Cancer stem cells are known to promote hepatocellular carcinoma (HCC) initiation, metastasis and resistance. Here, the authors identify SCARB2 as a driver of tumour-initiating cells via enhanced MYC activity and evaluate the efficacy of targeting this interaction using an FDA approved drug, Polymyxin-B, in preclinical models of HCC.
- Feng Wang
- , Yang Gao
- & Ke Li
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Article
| Open Access
A chemical catalyst enabling histone acylation with endogenous acyl-CoA
Chemical catalysts that can promote physiologically important post-translational modifications acting as enzyme surrogates have not been reported. Here, the authors develop mBnA, a chemical catalyst that promotes histone lysine acylation in live cells by activating endogenous acyl-CoAs as the only acyl donors.
- Misuzu Habazaki
- , Shinsuke Mizumoto
- & Motomu Kanai
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Article
| Open Access
TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition
The E1A binding protein p300 and its close paralogue CREB-binding protein are transcriptional coactivators with intrinsic histone acetyltransferase activity. Here, the authors show that the TAZ2 domain of p300 has a HAT autoinhibitory function that is relieved upon binding of transcription factors.
- Longxia Xu
- , Hongwen Xuan
- & Xiaobing Shi
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Article
| Open Access
Loss of N-terminal acetyltransferase A activity induces thermally unstable ribosomal proteins and increases their turnover in Saccharomyces cerevisiae
N-terminal acetylation is a common modification with unclear function. Here, using multidimensional proteomics, the authors found that NatA-deficient yeast show increased ribosomal protein degradation and decreased ribosome thermostability, suggesting that N-terminal acetylation enhances proteome stability.
- Ulises H. Guzman
- , Henriette Aksnes
- & Jesper V. Olsen
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Article
| Open Access
Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle
The authors report that acetylation of cytochrome c on K39 acts as a molecular switch in ischemic skeletal muscle, but not other tissues, to increase respiration and prevent apoptosis. This gives skeletal muscle robust resilience to ischemia and ischemia-reperfusion injury.
- Paul T. Morse
- , Gonzalo Pérez-Mejías
- & Maik Hüttemann
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Article
| Open Access
K235 acetylation couples with PSPC1 to regulate the m6A demethylation activity of ALKBH5 and tumorigenesis
Deregulation of N6-methyladenosine (m6A) modification can contribute to the pathogenesis of cancers. Here the authors show that m6A demethylase ALKBH5 is acetylated at K235 by acetyltransferase KAT8 and interacts with RNA-binding protein PSCP1 to enhance m6A demethylation and promote tumorigenesis.
- Xiao-Lan Zhang
- , Xin-Hui Chen
- & Guang-Rong Yan
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Article
| Open Access
Cryo-EM structure of the Saccharomyces cerevisiae Rpd3L histone deacetylase complex
The Rpd3L HDAC complex is an ancient chromatin-modifying complex found in diverse eukaryotes. Here, authors describe the cryo-EM structure of the yeast complex and show that key features are preserved in the human complex.
- Avinash B. Patel
- , Jinkang Qing
- & Yuan He
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Article
| Open Access
Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma
BRD4-NUT’s bipartite binding and activation of p300 in NUT carcinoma nucleates a feed-forward spread of histone hyperacetylation and chromatin condensation that sustains aberrant pro-proliferation gene transcription and perpetual tumor cell growth.
- Di Yu
- , Yingying Liang
- & Lei Zeng
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Article
| Open Access
SIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice
Sirtuins have been reported to positively regulate brown adipose tissue thermogenesis. Here the authors report that brown adipocytic SIRT7 suppresses whole-body energy expenditure and thermogenesis in mice, potentially by attenuating batokine gene expressions and Ucp1 mRNA translation.
- Tatsuya Yoshizawa
- , Yoshifumi Sato
- & Kazuya Yamagata
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Article
| Open Access
CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.
- Aurélie de Thonel
- , Johanna K. Ahlskog
- & Valérie Mezger
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Article
| Open Access
SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks
SAMHD1 has a dNTPase-independent resection function in genome maintenance. Here the authors show that SAMHD1 is deacetylated at conserved K354 by SIRT1 to facilitate direct binding with ssDNA to promote DNA end resection and homologous recombination.
- Priya Kapoor-Vazirani
- , Sandip K. Rath
- & David S. Yu
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Matters Arising
| Open Access
Pitfalls in using phenanthroline to study the causal relationship between promoter nucleosome acetylation and transcription
- Sevil Zencir
- , Daniel Dilg
- & Benjamin Albert
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Article
| Open Access
Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43
TDP-43 is a nucleic acid binding protein, whose insoluble aggregates are neuropathological hallmarks of specific subsets of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Post-translational modifications and acetylation of TDP-43 impact its interaction with RNA, its localization in the cells, and are linked to disease. Using antibodies generated against TDP-43 lysine acetylation sites, sirtuin-1 was found to potently deacetylate amber suppressed [acK136]TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding as well as phase separation and aggregation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
- Jorge Garcia Morato
- , Friederike Hans
- & Philipp J. Kahle
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Article
| Open Access
Lysine acetylation regulates the interaction between proteins and membranes
Lysine acetylation regulates the function of soluble proteins in vivo, yet it remains largely unexplored whether lysine acetylation regulates the function of membrane proteins. Here, the authors map lysine acetylation predominantly in membrane-interaction regions in peripheral membrane proteins and show with three candidate proteins how lysine acetylation is a regulator of membrane protein function.
- Alan K. Okada
- , Kazuki Teranishi
- & Ralf Langen
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Article
| Open Access
Acetylation of PAX7 controls muscle stem cell self-renewal and differentiation potential in mice
The acetyltransferase MYST1 stimulated by acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD+, regulate PAX7 acetylation in muscle stem cells, which in turn, regulates stem cell self-renewal and regeneration following injury in mouse skeletal muscle.
- Marie-Claude Sincennes
- , Caroline E. Brun
- & Michael A. Rudnicki
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Article
| Open Access
Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism
Histone acetylations are important epigenetic marks for transcriptional activation and respond to metabolic changes. Here the authors develop a lifespan screen and show that inactivation of the histone deacetylase complex activates longevity and protects against stress via trehalose metabolism.
- Ruofan Yu
- , Xiaohua Cao
- & Weiwei Dang
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Article
| Open Access
Rpd3/CoRest-mediated activity-dependent transcription regulates the flexibility in memory updating in Drosophila
The flexibility of memory updating may be determined in the initial memory consolidation process. Here, the authors show the proteomic changes of the transcriptional repressor complexes required for initial memory consolidation and influencing the flexibility of future memory updating.
- Mai Takakura
- , Reiko Nakagawa
- & Yukinori Hirano
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Article
| Open Access
Transcription shapes genome-wide histone acetylation patterns
Histone acetylation is a ubiquitous hallmark of transcription. Here the authors provide evidence that the majority of histone acetylation is dependent on transcription, specifically due to the requirement of RNAPII for the recruitment and activity of histone acetyltransferases.
- Benjamin J. E. Martin
- , Julie Brind’Amour
- & LeAnn J. Howe
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Article
| Open Access
CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks
Chromatin is dynamically remodeled in response to DNA damage in favour of repair. Here the authors reveal how the chromatin remodeler CHD7 and chromatin binding protein 53BP1 regulate distinct DNA repair pathways.
- Magdalena B. Rother
- , Stefania Pellegrino
- & Haico van Attikum
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Article
| Open Access
Divergent architecture of the heterotrimeric NatC complex explains N-terminal acetylation of cognate substrates
The conserved eukaryotic heterotrimeric NatC complex co-translationally acetylates the N-termini of numerous target proteins. Here, the authors provide insights into the catalytic mechanism of NatC by determining the crystal structures of Saccharomyces cerevisiae NatC in the absence and presence of cofactors and peptide substrates and reveal the molecular basis of substrate binding by further biochemical analyses.
- Stephan Grunwald
- , Linus V. M. Hopf
- & Oliver Daumke
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Article
| Open Access
Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6
SIRT6 plays essential roles in metabolism, tumor suppression, and DNA repair through the deacetylation of histone substrates. Here the authors use biophysical methods to investigate the molecular basis for SIRT6 interaction with the nucleosome core particle.
- Wallace H. Liu
- , Jie Zheng
- & John M. Denu
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Article
| Open Access
Leucine regulates autophagy via acetylation of the mTORC1 component raptor
Leucine is a critical amino acid that inhibits autophagy. Here, the authors show that the leucine inhibits autophagy in most cell types, predominantly via its catabolite acetyl CoA, which drives acetylation of raptor, which activates mTORC1, a negative regulator of this catabolic process.
- Sung Min Son
- , So Jung Park
- & David C. Rubinsztein
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Article
| Open Access
FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku
The Ku complex, formed by XRCC5/6 heterodimer, binds to double strand break (DSB) ends, initiating non homologous end joining (NHEJ) and preventing homologous recombination (HR). Here, the authors reveal that FOXL2, a forkhead family transcriptional factor, directs DSB repair pathway choice by acetylation-dependent binding to Ku.
- Hanyong Jin
- , Boeun Lee
- & Jeehyeon Bae
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Article
| Open Access
Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress
The autophagy receptor p62 mediates the assembly and removal of ubiquitylated protein aggregates by forming p62 bodies. Here, the authors identify an acetylation-dependent mechanism that regulates formation and autophagic clearance of p62 bodies under nutrient-deficient conditions.
- Zhiyuan You
- , Wen-Xue Jiang
- & Wei Liu
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Article
| Open Access
Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24
Stat6 promotes M2 macrophage polarization. Here the authors characterize Trim24-CBP-Stat6 circuit regulating M2 macrophage polarization via Stat6 acetylation, and show it contributes to pro-tumorigenic macrophage activity in mice.
- Tao Yu
- , Shucheng Gan
- & Yichuan Xiao
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Article
| Open Access
Acetyl-CoA flux regulates the proteome and acetyl-proteome to maintain intracellular metabolic crosstalk
The Endoplasmic Reticulum acetylation machinery ensures proper quality control and disposal of newly folded proteins transiting the secretory pathway. Here, the authors show that this machinery acts as a metabolic regulator of acetyl-CoA homeostasis, impacting intracellular crosstalk.
- Inca A. Dieterich
- , Alexis J. Lawton
- & Luigi Puglielli
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Article
| Open Access
Acetylation regulates ribonucleotide reductase activity and cancer cell growth
Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates to provide dNTP precursors for DNA synthesis. Here the authors show that the availability of dNTPs, DNA replication, and cellular proliferation, are modulated by acetylation and deacetylation of RRM2 by KAT7 and Sirt2 respectively.
- Guo Chen
- , Yin Luo
- & Xingming Deng
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Article
| Open Access
ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects
Huntington’s disease leads to mitochondrial fragmentation and bioenergetic failure, although how the two events are connected is poorly understood. Here, Zhao et al. identify ATAD3A as a molecular linker and show that a peptide inhibitor of ATAD3A oligomerization suppresses HD phenotypes.
- Yuanyuan Zhao
- , Xiaoyan Sun
- & Xin Qi
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Article
| Open Access
Analysis of human acetylation stoichiometry defines mechanistic constraints on protein regulation
Many human proteins are regulated by lysine acetylation, but the degree of acetylation at individual sites is poorly characterized. Here, the authors measure acetylation stoichiometry in the HeLa cell proteome, providing a resource to assess mechanistic constraints on acetylation-mediated protein regulation.
- Bogi Karbech Hansen
- , Rajat Gupta
- & Brian T. Weinert
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Article
| Open Access
Tip60- and sirtuin 2-regulated MARCKS acetylation and phosphorylation are required for diabetic embryopathy
Neural tube defects can arise from high glucose levels caused by maternal diabetes, and MARCKS is required for neural tube closure. Here, Yang et al. show that acetylation and phosphorylation of MARCKS in hyperglycemic conditions causes mitochondrial and ER stress, leading to neural tube defects.
- Penghua Yang
- , Cheng Xu
- & Peixin Yang
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Article
| Open Access
The ZZ-type zinc finger of ZZZ3 modulates the ATAC complex-mediated histone acetylation and gene activation
Histones are recognized by epigenetic readers, which play essential roles in regulation of chromatin and transcription. Here the authors provide evidence that the ZZ-type zinc finger domain of ZZZ3 functions as a reader of histone H3, which is required for the ATAC complex-mediated maintenance of histone acetylation and gene activation.
- Wenyi Mi
- , Yi Zhang
- & Xiaobing Shi
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Article
| Open Access
Mutually exclusive acetylation and ubiquitylation of the splicing factor SRSF5 control tumor growth
Changes in glucose metabolism can lead to tumor development, but the involvement of splicing factors is unclear. Here, the authors screened for SR proteins and identified SRSF5 stability is enhanced in response to glucose elevation to promote alternative splicing of CCAR1 which facilitates tumor growth.
- Yuhan Chen
- , Qingyang Huang
- & Lingqiang Zhang
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Article
| Open Access
Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate
The acetyltransferase Tip60 mediates signaling pathways by acetylating non-histone proteins. Here the authors show that fatty acids induce Tip60–dependent acetylation of phosphatidic acid phosphatase lipin1 which, then, translocates to the ER and generates diacylglycerols for triglyceride synthesis.
- Terytty Yang Li
- , Lintao Song
- & Sheng-Cai Lin
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Article
| Open Access
CoA synthase regulates mitotic fidelity via CBP-mediated acetylation
The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here the authors show that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a mechanism that ensures faithful mitosis.
- Chao-Chieh Lin
- , Mayumi Kitagawa
- & Jen-Tsan Chi
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Article
| Open Access
Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy
Mutations in glycyl-tRNA synthetase (GlyRS) cause Charcot-Marie-Tooth disease, a neuromuscular disorder characterized by axonal degeneration. Here the authors show that mutant GlyRS interacts with histone deacetylase 6, resulting in increased deacetylation of α-tubulin and axonal transport deficits.
- Zhongying Mo
- , Xiaobei Zhao
- & Xiang-Lei Yang
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Article
| Open Access
Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis
Enhanced glycolysis in cancer cells has been associated with protection from DNA damage. Here the authors show that DNA damaging signals induce acetylation of PFKFB3 at lysine K472 and promote its cytosolic accumulation, which enhances glycolysis, resulting in protection from cisplatin-induced cell death.
- Fu-Long Li
- , Jin-Ping Liu
- & Hai-Xin Yuan
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Article
| Open Access
Critical role of the HDAC6–cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect
Histone deacetylase (HDAC) inhibitors, a class of cancer therapeutics, cause thrombocytopenia via an unknown mechanism. Here, the authors show that HDAC6 inhibition impairs proplatelet formation in human megakaryocytes, and show that this is linked to hyperacetylation of the actin-binding protein cortactin.
- Kahia Messaoudi
- , Ashfaq Ali
- & Najet Debili
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Article
| Open Access
Role of influenza A virus NP acetylation on viral growth and replication
Post-translational modifications of influenza A virus proteins can regulate virus replication, but the effect of nucleoprotein (NP) acetylation is not known. Here, Giese et al. identify four NP lysine residues that are acetylated in infected cells and study their role in polymerase activity and virion release.
- Sebastian Giese
- , Kevin Ciminski
- & Martin Schwemmle
Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress