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| Open AccessAuranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes
Decreased activity of the E1 ubiquitin-activating enzyme UBA1 can contribute to aging and diseases like Alzheimer’s and VEXAS syndrome. Here, the authors found that auranofin, a rheumatoid arthritis drug, can significantly boost UBA1 activity.
- Wenjing Yan
- , Yongwang Zhong
- & Shengyun Fang
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Article
| Open AccessA HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis
Cholesterol synthesis is highly oxygen consuming but how it is regulated by oxygen levels has not been clear. Here, Dickson et al. identify a HIF-independent, oxygen-sensing pathway for controlling cholesterol synthesis in human cells involving hypoxic-mediated degradation of SREBP2.
- Anna S. Dickson
- , Tekle Pauzaite
- & James A. Nathan
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Article
| Open AccessGetting personal with epigenetics: towards individual-specific epigenomic imputation with machine learning
The authors present eDICE, an attention-based model that enables accurate imputation of missing portions of the observed epigenetic landscape, and show that eDICE can be used to predict individualspecific epigenomic variation in the EN-TEx dataset.
- Alex Hawkins-Hooker
- , Giovanni Visonà
- & Gabriele Schweikert
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Article
| Open AccessERFVII action and modulation through oxygen-sensing in Arabidopsis thaliana
Oxygen is essential for plant life. Here the authors define new functions and components of the plant oxygen sensing mechanism providing an understanding of the biochemistry of sensing and physiological responses allowing plant roots to survive in the soil.
- Agata Zubrycka
- , Charlene Dambire
- & Michael J. Holdsworth
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Article
| Open AccessCullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality, and there is no specific drug to treat it. Here, the authors show that the AR-CAND1-ACAA2 axis regulates the development of NAFLD, and enhancing the function of CAND1 is a promising strategy for the development of a therapeutic agent for NAFLD.
- Xiang Huang
- , Xin Liu
- & Zhenwei Pan
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Article
| Open AccessLoss 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 AccessIL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation
The turnover of interleukin-1β, a cytokine that plays important roles in both physiologic and pathologic inflammatory processes, is regulated by proteolytic maturation of the pro-form and by ubiquitin-mediated degradation. Here authors identify the specific ubiquitin E3 ligases that form an active complex with UBE2L3, a ubiquitin conjugating enzyme, that target pro-IL-1β for proteasomal breakdown.
- Vishwas Mishra
- , Anna Crespo-Puig
- & Avinash R. Shenoy
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Article
| Open AccessRegulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3
Here the authors identify that PARP1 maintains genome integrity by regulating replication fork recovery by break-induced replication. Mechanistically, this is achieved through MRE11-dependent PARP1 activation and site-specific ADP-ribosylation of PolD3.
- Frederick Richards
- , Marta J. Llorca-Cardenosa
- & Nicholas D. Lakin
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Article
| Open AccessA seven-transmembrane methyltransferase catalysing N-terminal histidine methylation of lytic polysaccharide monooxygenases
N-terminal histidine methylation modification has only been observed on certain fungal proteins. Here, the authors identify and validate the methyltransferase responsible for this modification through the combination of mass spectrometry-based proteomics and CRISPR/Cas9.
- Tanveer S. Batth
- , Jonas L. Simonsen
- & Jesper V. Olsen
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Article
| Open AccessCytochrome 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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Comment
| Open AccessLimited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies
Protein lysine methylation plays important biological roles but its experimental characterization is limited by the lack of suitable mimetics of methylated and unmethylated lysine among the natural amino acids. Here, we summarize the consequent challenges and discuss alternative approaches for biochemical and cellular lysine methylation studies.
- Sara Weirich
- & Albert Jeltsch
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Article
| Open AccessHistone H1 facilitates restoration of H3K27me3 during DNA replication by chromatin compaction
Liu et al. investigated the dynamic re-establishment of H3K27me3 on nascent DNA during DNA replication. They found H1-mediated chromatin compaction facilitates the propagation and restoration of H3K27me3 after DNA replication.
- Cuifang Liu
- , Juan Yu
- & Guohong Li
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Article
| Open AccessASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair
Due to the naturally dense packing of the genome, DNA repair factors encounter a topologically very intricate cellular context. We describe how the human ASH1L protein navigates excision repair factors to accelerate their search for DNA lesions.
- Corina Maritz
- , Reihaneh Khaleghi
- & Hanspeter Naegeli
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Article
| Open AccessSUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways
Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.
- Dan Tan
- , Meiping Lu
- & Ximei Wu
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Article
| Open AccessK235 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 AccessTargeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer therapy. Here, the authors identify pevonedistat, NEDD8 inhibitor, as synergistic with irinotecan by blocking neddylation-activated ubiquitin/proteasomal degradation of TOP1-DPC.
- Yilun Sun
- , Simone A. Baechler
- & Yves Pommier
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Article
| Open AccessUSP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice
The redox status of a cell is regulated through a number of mechanisms, chief among these is the KEAP1-mediated ubiquitination and degradation of NRF2. Here the authors show that KEAP1 itself is ubiquitinated and degraded in a process that is opposed by the ubiquitin-specific protease USP25.
- Changzhou Cai
- , Huailu Ma
- & Jiewei Wang
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Article
| Open AccessStructural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
PEAK pseudokinases are emerging disease targets, which regulate cell migration and proliferation through protein scaffolding. Here, the authors present the cryo-EM structure of the PEAK3/14-3-3 complex and reveal how 14-3-3 modulates PEAK3 localization and protein-protein interactions.
- Hayarpi Torosyan
- , Michael D. Paul
- & Kliment A. Verba
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| Open AccessStructural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling
The PEAK family of pseudokinases are key hubs in cellular signalling, including cell motility and cancer. Here, the authors characterise how PEAK proteins interact with the adapter proteins CrkII and Grb2 and regulatory scaffold protein 14-3-3, to achieve functional signalling assemblies.
- Michael J. Roy
- , Minglyanna G. Surudoi
- & Isabelle S. Lucet
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Article
| Open AccessHybrid-DIA: intelligent data acquisition integrates targeted and discovery proteomics to analyze phospho-signaling in single spheroids
Standard mass spectrometry analyses often miss key targets required for phospho-signalling reconstruction. Here, authors present an intelligent data acquisition strategy that combines discovery and targeted analysis in one run and apply it to maximize the information from single spheroids drug screenings.
- Ana Martínez-Val
- , Kyle Fort
- & Jesper V. Olsen
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Article
| Open AccessCryo-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 AccessDecoding protein methylation function with thermal stability analysis
Methylation is a common modification that affects protein function but, compared to other modifications, our knowledge is limited. Here, the authors use a method based on thermal stability to study how protein methylation regulates processes such as mRNA binding proteins and chromosome compaction.
- Cristina Sayago
- , Jana Sánchez-Wandelmer
- & Javier Munoz
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Article
| Open AccessAn Aurora B-RPA signaling axis secures chromosome segregation fidelity
RPA is a master coordinator of DNA metabolism. Here, authors uncover that RPA is regulated by an Aurora B-signaling circuit that is critical for chromosome segregation in mitosis. Distinct phosphorylation of RPA70 modulates accessibility of RPA domains.
- Poonam Roshan
- , Sahiti Kuppa
- & Sofia Origanti
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Article
| Open AccessRedefining the role of AMPK in autophagy and the energy stress response
According to the current understanding in the field, AMPK promotes autophagy by activating ULK1 during energy stress. Here, authors show that AMPK is indeed a negative regulator of ULK1 and it suppresses autophagy in energy depleted cells.
- Ji-Man Park
- , Da-Hye Lee
- & Do-Hyung Kim
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Article
| Open AccessMoS2 nanopore identifies single amino acids with sub-1 Dalton resolution
Protein sequencing is one of the key aims of the nanopore field. Working toward this goal, here the authors report the direct identification of single amino acids in MoS2 nanopores with sub-1 Dalton resolution, as well as the discrimination of the amino acid isomers and amino acid phosphorylation.
- Fushi Wang
- , Chunxiao Zhao
- & Jiandong Feng
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Article
| Open AccessPRMT1 mediated methylation of cGAS suppresses anti-tumor immunity
cGAS/STING mediated immunity is linked to the anti-tumor response, but how tumor-intrinsic cGAS signals are countered during tumorigenesis and immune evasion is poorly understood. Here the authors show PRMT1 suppresses the anti-tumor immune response via arginine methylation of cGAS.
- Jing Liu
- , Xia Bu
- & Wenyi Wei
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Article
| Open AccessSmall-sample learning reveals propionylation in determining global protein homeostasis
The development of a new smallsample learning framework, KprFunc, leads to the discovery of an important role for lysine propionylation in determining global protein homeostasis, mediated by a critical propionylation site on histone H2B, H2BK17pr.
- Ke Shui
- , Chenwei Wang
- & Yu Xue
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Article
| Open AccessMolecular basis for recognition and deubiquitination of 40S ribosomes by Otu2
Otu2-driven deubiquitylation of ribosomal protein eS7 impacts translational efficiency. Here, the authors provide the molecular basis for recognition of monoubiquitinated eS7 on 40S and give mechanistic insights into Otu2’s role in translation reset.
- Ken Ikeuchi
- , Nives Ivic
- & Roland Beckmann
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Article
| Open AccessBroad phosphorylation mediated by testis-specific serine/threonine kinases contributes to spermiogenesis and male fertility
Testis-specific serine/threonine kinases have been associated with male infertility, but the mechanism for this connection is unclear. Here they identify a Drosophila homolog, dTSSK, which is essential for male fertility in fruit flies and has functionally conserved catalytic activity with human TSSKs.
- Xuedi Zhang
- , Ju Peng
- & Guanjun Gao
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Article
| Open AccessMetabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma
The molecular mechanisms underlying MYC overexpression in group 3 medulloblastoma remain to be explored. Here, the authors highlight the involvement of the mitochondrial pyruvate carrier- SOD2 signalling pathway in the regulation of MYC protein abundance.
- Emma Martell
- , Helgi Kuzmychova
- & Tanveer Sharif
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Article
| Open AccessA link between STK signalling and capsular polysaccharide synthesis in Streptococcus suis
Serine/threonine kinases (STKs) regulate the synthesis of capsular polysaccharide in bacteria through unclear mechanisms. Here, Tang et al. identify a protein that is phosphorylated by an STK and modulates the activity of a phosphoregulatory system in Streptococcus suis, thus linking STKs to capsular polysaccharide synthesis.
- Jinsheng Tang
- , Mengru Guo
- & Hongjie Fan
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Article
| Open AccessUSP7 controls NGN3 stability and pancreatic endocrine lineage development
Tightly controlled NGN3 expression is essential for endocrine cell generation in the developing pancreas, with dysregulation leading to hyperglycemia in mice. Here they identify USP7 as a key post-translational regulator of NGN3 stability and show that this axis is required for endocrine development and beta-cell differentiation.
- Teodora Manea
- , Jessica Kristine Nelson
- & Rocio Sancho
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Article
| Open AccessDNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC
DNA polymerase 1 (POLD1) has an important role in DNA damage repair and is frequently upregulated in cancer. Here, the authors report a non-canonical role of POLD1 wherein it stabilises MYC protein, creating a positive feedback loop with POLD1 expression and driving bladder cancer progression and metastasis.
- Yejinpeng Wang
- , Lingao Ju
- & Xinghuan Wang
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Article
| Open AccessTranscription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing
Antibiotic resistance in Staphylococcus aureus is increasingly emerging. Here, Shu et al demonstrate that transcriptional regulation by S-nitrosylation underlies vancomycin resistance.
- Xueqin Shu
- , Yingying Shi
- & Baolin Sun
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Article
| Open AccessDephosphocholination by Legionella effector Lem3 functions through remodelling of the switch II region of Rab1b
During infection, the Legionella effector Lem3 removes a phosphocholine moiety from the human protein Rab1. Here, the authors present the crystal structure of the stabilised Lem3:Rab1b complex, revealing the catalytic mechanism and substrate recognition of PPM phosphatases shaped Lem3.
- Marietta S. Kaspers
- , Vivian Pogenberg
- & Aymelt Itzen
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Article
| Open AccessHsp90 provides a platform for kinase dephosphorylation by PP5
PP5 requires the molecular chaperone Hsp90 to dephosphorylate CRaf kinase and the Hsp90 cochaperone Cdc37. Here, authors show how Hsp90 acts as a platform to allow for targeted dephosphorylation by PP5.
- Maru Jaime-Garza
- , Carlos A. Nowotny
- & David A. Agard
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Article
| Open AccessTrim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates
TRIM21 mediates intracellular antibody immunity and is exploited for targeted protein degradation using Trim-Away technology. Here, the authors dissect the ubiquitination requirements for Trim-Away, providing an explanation for how TRIM21 can target diverse substrates for degradation.
- Leo Kiss
- , Tyler Rhinesmith
- & Leo C. James
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Article
| Open AccessWorkflow enabling deepscale immunopeptidome, proteome, ubiquitylome, phosphoproteome, and acetylome analyses of sample-limited tissues
Patient samples are often available in limited amounts, restricting the number of possible omics analyses. Here the authors present MONTE, a workflow that enables serial HLA-I and HLA-II immunopeptidome, ubiquitylome, proteome, phosphoproteome, and acetylome data collection from patient samples.
- Jennifer G. Abelin
- , Erik J. Bergstrom
- & Steven A. Carr
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Article
| Open AccessArabidopsis TRB proteins function in H3K4me3 demethylation by recruiting JMJ14
TRB proteins have been shown to recruit PRC2 for H3K27me3 deposition. This work shows that TRBs also recruit JMJ14 to remove H3K4me3, demonstrating that TRBs silence the target genes via a combinatorial histone modification mechanism.
- Ming Wang
- , Zhenhui Zhong
- & Steven E. Jacobsen
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Article
| Open AccessEnhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models.
- Themis Thoudam
- , Dipanjan Chanda
- & In-Kyu Lee
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Article
| Open AccessPaternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring
Anti-folate drugs, such as methotrexate, have been largely prohibited for pregnant women because of the teratogenic effect on their descendant. Here, the authors report a intergenerational mechanism by why paternal methotrexate exposure causes craniofacial defects on their offspring.
- Nagif Alata Jimenez
- , Mauricio Castellano
- & Pablo H. Strobl-Mazzulla
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Article
| Open AccessSystematic characterization of chromodomain proteins reveals an H3K9me1/2 reader regulating aging in C. elegans
Chromodomains mainly function as histone methyl-lysine readers to regulate gene expression. Here the authors delineate a functional map of chromodomain proteins and identify an H3K9me1/2 writer, MET-2, and reader, CEC-5, that are required for the normal lifespan of C. elegans.
- Xinhao Hou
- , Mingjing Xu
- & Xuezhu Feng
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Article
| Open AccessN6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice
N6-methyladenosine (m6A) methylation of RNA is a common type of RNA modification that regulates gene expression. Here, the authors report m6A methylation of serpin 2 A negatively regulates inflammation and reduces heart dysfunction in the setting of sepsis.
- Xiangyu Wang
- , Yan Ding
- & Jie Du
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Article
| Open AccessStructural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
Tumour suppressors are inhibited in cancers and their reactivation could provide novel therapy opportunities. Here, the authors study the structural mechanism by which human tumour suppressor Protein Phosphatase 2A is inhibited in breast cancer cells by the oncoprotein CIP2A.
- Karolina Pavic
- , Nikhil Gupta
- & Jukka Westermarck
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Article
| Open AccessSsu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation
Brown adipose tissue (BAT) is a specialized thermogenic organ that undergoes high demands of protein synthesis during thermogenic adaptation. Here, the authors show that the cold responsive phosphatase Ssu72 is required for mRNA translation that affects thermogenic adaptation in BAT.
- Eun-Ji Park
- , Hyun-Soo Kim
- & Chang-Woo Lee
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Article
| Open AccessCitrullination modulates antigen processing and presentation by revealing cryptic epitopes in rheumatoid arthritis
Antibodies directed against citrullinated proteins are commonly found in patients with rheumatoid arthritis. Here, the authors show that citrullination alters the peptide repertoire presented to T cells by altering protease cleavage and inducing protein destabilization, thereby exposing cryptic epitopes.
- Ashley M. Curran
- , Alexander A. Girgis
- & Erika Darrah
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Article
| Open AccessPHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma
The role of protein arginine methylation in serine metabolism of cancer cells in hepatocellular carcinoma (HCC) remains to be explored. Here, the authors show that phosphoglycerate dehydrogenase (PHGDH) is activated by PRMT1-mediated R236 methylation, promoting serine synthesis, redox homeostasis and HCC growth.
- Kui Wang
- , Li Luo
- & Canhua Huang
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Article
| Open AccessIdentification of global inhibitors of cellular glycosylation
Here, the authors discover small molecules that inhibit glycosylation processes that occur in the Golgi apparatus of cells. The molecules reversibly inhibit formation of elaborate glycan structures without affecting secretion of glycoproteins.
- Daniel Madriz Sørensen
- , Christian Büll
- & Yoshiki Narimatsu
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Article
| Open AccessTRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models
The molecular mechanisms determining the response to radiotherapy remain incompletely understood. Here, the authors demonstrate that the E3 ubiquitin ligase and intracellular Fc receptor, TRIM21, impairs CD8+ T cell responses in nasopharyngeal carcinoma tumour models following ionizing radiation.
- Jun-Yan Li
- , Yin Zhao
- & Na Liu