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| Open AccessSequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity
Here, the authors show that GalNAc-T3 and T7 regulate furin cleavage of the SARS-CoV-2 spike protein via O-glycosylation. This influences viral assembly and infection, highlighting glycosylation as a host defense mechanism.
- Shengjun Wang
- , Wei Ran
- & Yang Mao
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| Open AccessThe great escape: a Shigella effector unlocks the septin cage
Shigella, an important human pathogen, can secrete effector proteins to invade host cells and evade mechanisms of cell-autonomous immunity. In a new manuscript published in Nature Communications, Xian et al. report that the Shigella kinase effector OspG promotes the ubiquitination of septin cytoskeletal proteins to evade cage entrapment.
- Ana T. López-Jiménez
- , Gizem Özbaykal Güler
- & Serge Mostowy
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| Open AccessPost-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress
Here the authors show that the human transcription elongation factor AF9, part of Super Elongation Complex (SEC), undergoes oligomerization which can be reverted by post-translational modification in regulation of global transcription.
- Prathama Talukdar
- , Sujay Pal
- & Debabrata Biswas
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Article
| Open AccessProteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis
MAPK-driven tumorigenesis is often related to epithelial dedifferentiation but the regulatory mechanism is less clear. Here, the authors show that MAPK activation upregulates USP15 to promote deubiquitylation and stability of TBX3, a transcription factor implicated in thyroid development and differentiation, driving tumorigenesis in a BRAFV600E thyroid tumor model.
- Zhenlei Zhang
- , Yufan Wu
- & Li Zhao
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Article
| Open AccessMethylation of ESCRT-III components regulates the timing of cytokinetic abscission
Methylation of CHMP2B regulates abscission timing by modulating ESCRT-III dynamics during cytokinesis. This methylation also plays a role in HIV-1 budding, highlighting the broader significance of ESCRT-III methylation.
- Aurélie Richard
- , Jérémy Berthelet
- & Souhila Medjkane
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Article
| Open AccessA conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22
The assembly integrity of dimeric CRL3 E3 ligases are important in various physiological and pathological processes. Here, the authors show that an evolutionarily conserved CUL3 N-terminal motif contributes to both the assembly and activity of dimeric CRL3 E3 ligases.
- Weize Wang
- , Ling Liang
- & Yuxin Yin
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Article
| Open AccessLoss of NEDD8 in cancer cells causes vulnerability to immune checkpoint blockade in triple-negative breast cancer
NEDD8 is a ubiquitin-like protein that governs protein neddylation, previously demonstrated to be essential for cell survival. Here the authors show that NEDD8 loss in breast cancer cells is associated with enhanced immunogenicity and increased sensitivity to PD-1 blockade in preclinical cancer models.
- Irineos Papakyriacou
- , Ginte Kutkaite
- & Yumeng Mao
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Article
| Open AccessHBO1 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 AccessOxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3
Oxygen is an essential requirement for aerobic organisms. Here the authors explore the role of oxygen in the antiviral innate response in multiple models of infection and suggest oxygen enhances the antiviral innate response via EGLN1 hydroxylation of IRF3.
- Xing Liu
- , Jinhua Tang
- & Wuhan Xiao
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Article
| Open AccessTyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity
Coactivator-associated arginine methyltransferase 1 (CARM1) is an important target in hematologic malignancies. In this work, the authors show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates CARM1 which regulates its methyltransferase activity and alters its target specificity.
- Hidehiro Itonaga
- , Adnan K. Mookhtiar
- & Stephen D. Nimer
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Article
| Open AccessReciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry
Unveiling the regulation of mitotic protein degradation is crucial for cancer therapy. Here, the authors reveal that a reciprocal inhibition of PIN1-APC/CCDH1 controls the cell cycle and mitotic protein degradation, offering a synergistic anti-tumor strategy.
- Shizhong Ke
- , Fabin Dang
- & Kun Ping Lu
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Article
| Open AccessDynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2
Maintaining a healthy nuclear proteome during DNA damage is important but its regulation is poorly understood. The authors here show that a SUMO modification of the small heat shock protein Btn2 regulates yeast nuclear protein sequestration during stress.
- Arun Kumar
- , Veena Mathew
- & Peter C. Stirling
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Article
| Open AccessNardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer
Polo-like kinase 3 (Plk3) has a tumor suppressive role through the induction of apoptosis, however, the mechanism underlying its activation is unclear. Here, in pancreatic cancer, the authors show that activation of Plk3 is dependent on its cleavage into p41Plk3, by the metalloendopeptidase nardilysin.
- Jie Fu
- , Jianhua Ling
- & Paul J. Chiao
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Article
| Open AccessPathogenic mutations of human phosphorylation sites affect protein–protein interactions
Here the authors characterise the impact of phosphorylation site mutations in intrinsically disordered regions (IDRs) on protein-protein interactions, highlighting the critical role of phosphorylation of IDRs in health and disease.
- Trendelina Rrustemi
- , Katrina Meyer
- & Matthias Selbach
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Article
| Open AccessSystematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis
Authors perform an in vivo mass spectrometry-based interactome analysis of HOIL-1-interacting protein, a key component of linear ubiquitination assembly complex.
- Yesheng Fu
- , Lei Li
- & Lingqiang Zhang
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Article
| Open AccessDbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination
The repair of DNA double strand breaks is strictly controlled during the cell cycle by the CDK kinase. Here the authors identify the DDK kinase as a second major regulator for this cell cycle regulation and elucidate its functional targets.
- Lorenzo Galanti
- , Martina Peritore
- & Boris Pfander
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Article
| Open AccessInvolution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway
Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution. Here, the authors demonstrate that physiologic aging induced involution and thermogenic dysfunction result from pyroptotic signalling activation.
- Xiaofan Yu
- , Gabrielle Benitez
- & Daorong Feng
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Article
| Open AccessLoss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing
Mutations in protein arginine methyltransferase 9 (PRMT9) are linked to intellectual disability. Here, the authors show that mutant PRMT9 fails to methylate its primary substrate SF3B2, causing aberrant RNA splicing and abnormal synapse development.
- Lei Shen
- , Xiaokuang Ma
- & Yanzhong Yang
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Article
| Open AccessCasein kinase II promotes piRNA production through direct phosphorylation of USTC component TOFU-4
How the production of piRNA is regulated remains elusive. Here the authors showed that casein kinase II mediated direct phosphorylation of USTC component TOFU-4 promotes piRNA production.
- Gangming Zhang
- , Chunwei Zheng
- & Craig Mello
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Article
| Open AccessIon mobility-tandem mass spectrometry of mucin-type O-glycans
Currently, only a few specialized labs can characterize O-glycans. The present study couples high-resolution ion mobility spectrometry with tandem mass spectrometry to efficiently identify complex O-glycan structures in clinical samples.
- Leïla Bechtella
- , Jin Chunsheng
- & Kevin Pagel
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Article
| Open AccessThe aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open AccessA structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins
Here, the authors identify a small molecule degrader (XL44) for hRpn13 and solve the XL44-hRpn13 structure. XL44 induces apoptosis in myeloma cells with hRpn13 dependency and also targets KEN box proteins PCLAF and RRM2. Loss of hRpn13 and PCLAF abrogates XL44 restriction of cell viability.
- Xiuxiu Lu
- , Monika Chandravanshi
- & Kylie J. Walters
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Article
| Open AccessVCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates
p97/VCP, a nexus of the ubiquitin system, recognizes and unfolds ubiquitylated substrates via multiple cofactors. Here, the authors identify VCF1, a nuclear cofactor promoting p97 recruitment to, and proteasomal degradation of, ubiquitylated targets.
- Ann Schirin Mirsanaye
- , Saskia Hoffmann
- & Niels Mailand
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Article
| Open AccessCryo-EM structures of type IV pili complexed with nanobodies reveal immune escape mechanisms
Bacterial type IV pili are filamentous cell surface structures and candidate targets for vaccine development. Here, authors determine how antibodies interact with pili at the structural level providing insight into immune escape mechanisms and potential countermeasures.
- David Fernandez-Martinez
- , Youxin Kong
- & Guillaume Duménil
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Article
| Open AccessTherapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability
MYC oncogene promotes tumourigenesis by coordinating cancer cell proliferation with metabolic adaptation to the consequent excessive oxidative stress. Here, the authors show that nudix hydrolase 1 (NUDT1) is a MYC-driven metabolic vulnerability and generate a NUDT1 protein degrader to treat preclinical MYC-associated cancer.
- Minhui Ye
- , Yingzhe Fang
- & Guoliang Qing
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Article
| Open AccessNME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia
NME3 is a member of NDPK family. Here, Chen et. al., discover that histidine phosphorylatable NME3 is required for hypoxia-induced mitophagy via PA-dependent interaction with Drp1, which is protected from MUL1-mediated ubiquitination for mitophagy.
- Chih-Wei Chen
- , Chi Su
- & Zee-Fen Chang
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Article
| Open AccessBiallelic 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 AccessMicrotubule 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 AccessDJ-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 AccessSpatiotemporal 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 AccessThe Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation
The Eyes Absent proteins (EYA1-4) are a group of tyrosine phosphatases. Here, the authors report a signalling pathway in which EYA4 and EYA1 dephosphorylate Polo-like kinase 1 (PLK1) at pY445 to support PLK1 activation and mitosis.
- Christopher B. Nelson
- , Samuel Rogers
- & Hilda A. Pickett
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Article
| Open AccessStructure-guided engineering enables E3 ligase-free and versatile protein ubiquitination via UBE2E1
Ubiquitin E3 ligases are key to accessing ubiquitinated proteins, but only a few substrates have defined E3 ligases. Here, the authors reveal the mechanism of naturally occurring E3-independent ubiquitination and develop an E3-free enzymatic strategy for the versatile generation of ubiquitinated proteins.
- Xiangwei Wu
- , Yunxiang Du
- & Lei Liu
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Article
| Open AccessUbiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates
Upon cold exposure, two types of thermogenic fat cells, brown and beige adipocytes, are sequentially activated. Here, the authors show that E3 ubiquitin ligase RNF20 coordinates the sequential thermogenic activation through fat depot specific substrates.
- Yong Geun Jeon
- , Hahn Nahmgoong
- & Jae Bum Kim
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Article
| Open AccessThe CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.
- Xiaofeng Liao
- , Wenxue Li
- & Dianqing Wu
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Article
| Open AccessThe phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling
The T cell receptor signalosome integrates multiple positive and negative regulatory elements to finetune the response and limit harmful inflammation. Here authors show a regulatory cascade of T cell activation, in which DUSP22 negatively regulates UBR2, which is an activator of the kinase Lck via K63 ubiquitination.
- Ying-Chun Shih
- , Hsueh-Fen Chen
- & Tse-Hua Tan
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Article
| Open AccessN-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line
IgG molecules are glycosylated at a conserved asparagine residue of their constant region, and this modification is essential for the effector functions of their soluble form, such as complement activation and binding to Fcɣ receptors. Here authors show that in a model B-cell line, neither the expression nor the function of the membrane-bound form of IgG depend on glycosylation.
- Theresa Kissel
- , Veerle F. A. M. Derksen
- & René E. M. Toes
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Article
| Open AccessA role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding
Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.
- Haopeng Lin
- , Kunimasa Suzuki
- & Patrick E. MacDonald
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Article
| Open AccessTRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence
Here, the authors show that TRIM28-mediated SUMOylation of SARS-CoV-2 NP is critical for its liquid-liquid phase separation (LLPS) property and subsequent inhibition of innate antiviral immunity. The peptide NSIP-III is applied to unleash such connection by interfering TRIM28 and NP interaction.
- Jiang Ren
- , Shuai Wang
- & Long Zhang
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Article
| Open AccessCovalent PARylation of DNA base excision repair proteins regulates DNA demethylation
The PARylation activity of PARP recruits DNA repair proteins to damaged DNA, most likely via non-covalent protein-PAR interactions. Here, the authors show that PARP1 covalently PARylates base excision repair proteins to modulate their DNA transactions and thus promote active BER DNA demethylation.
- Simon D. Schwarz
- , Jianming Xu
- & Roland Steinacher
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Article
| Open AccessStabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Post-translational modifications including protein sumoylation is under specific regulation in glioma stem cells (GSCs). Here, the authors show that Pin1 is deubiquitinated and stabilized by USP34, which in turn promotes isomerization of Ubc9, leading to SUMO1-modified global hypersumoylation to maintain the tumorigenic capacity of GSCs.
- Qiuhong Zhu
- , Panpan Liang
- & Wenchao Zhou
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Article
| Open AccessThe Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival
Singh et al. show how the M. tuberculosis methyltransferase Rv2067c outsmarts host epigenetic machinery by methylating histone H3 prior to its assembly into nucleosomes, thereby ensuring the pathogen’s intracellular survival/success.
- Prakruti R. Singh
- , Venkatareddy Dadireddy
- & Valakunja Nagaraja
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Article
| Open AccessAutophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury
Understanding the role of GPX4 in cell ferroptosis at the interface of the inner cortex and medulla is crucial in the context of renal injury. Here, the authors demonstrate that the OTUD5 interaction with GPX4 is key in resisting ischemia/reperfusion-induced ferroptosis in renal cells, offering a new strategy for treating acute kidney injury.
- Li-Kai Chu
- , Xu Cao
- & Jun Liu
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Article
| Open AccessAcetylation 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 AccessMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57Kip2.
- Silvia Pomella
- , Matteo Cassandri
- & Rossella Rota
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Article
| Open AccessUbiquitination-mediated Golgi-to-endosome sorting determines the toxin-antidote duality of fission yeast wtf meiotic drivers
Meiotic drivers of the wtf family kill progeny lacking the driver by producing a toxin and an antidote. Here, authors reveal that ubiquitination-mediated sorting of the antidote prevents it from becoming toxic and enables it to neutralize the toxin.
- Jin-Xin Zheng
- , Tong-Yang Du
- & Li-Lin Du
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Article
| Open AccessProfiling ubiquitin signalling with UBIMAX reveals DNA damage- and SCFβ-Trcp1-dependent ubiquitylation of the actin-organizing protein Dbn1
Using Xenopus egg extracts, the authors developed a mass spectrometry method (UBIMAX) to identify proteins ubiquitylated in response to defined DNA lesions. Highlighting UBIMAX’s versatility, they describe the ubiquitylation of the actin regulator Dbn1 in response to DNA double-strand breaks.
- Camilla S. Colding-Christensen
- , Ellen S. Kakulidis
- & Michael L. Nielsen
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Article
| Open AccessRemodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases
Here, the authors show how the vDUB from the large tegument protein from the human herpes virus can reprogram translation in host cells by modulating the activity of the ribosome quality machinery and activating the integrated stress response.
- Jiangnan Liu
- , Noemi Nagy
- & Maria G. Masucci
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Article
| Open AccessNuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation
Zhen and colleagues show that nuclear cGAS represses L1 retrotransposition to stabilize the genome by enhancing the interaction between ORF2p and the E3 ligase TRIM41 upon DNA damage, which leads to the ubiquitination and degradation of ORF2p.
- Zhengyi Zhen
- , Yu Chen
- & Zhiyong Mao
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Article
| Open AccessThe assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination
The role that cellular bioenergetics plays in the early stages of Alzheimer’s disease is poorly understood. Here the authors describe structures of key OXPHOS assembly proteins, providing insights into how these pathways are interlinked and regulated.
- Lindsay McGregor
- , Samira Acajjaoui
- & Montserrat Soler-Lopez