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| Open AccessNon-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
In membranous nephropathy autoantibodies target podocytes of the kidney filter resulting in injury. Here the authors show that the ensuing proteostatic disturbances and proteinuria relate to aberrant interactions of non-functional UCH-L1 enzyme with the proteasome, curtailing its capacity.
- Julia Reichelt
- , Wiebke Sachs
- & Catherine Meyer-Schwesinger
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Article
| Open AccessTryptase β regulation of joint lubrication and inflammation via proteoglycan-4 in osteoarthritis
Altered expression and function of the extracellular matrix protein PRG4 have been associated with osteoarthritis. Here, the authors show that mast cell tryptase β cleaves PRG4, resulting in a reduction of lubrication and activation of inflammation in this context.
- Nabangshu Das
- , Luiz G. N. de Almeida
- & Antoine Dufour
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Article
| Open AccessDNA replication initiation factor RECQ4 possesses a role in antagonizing DNA replication initiation
RECQ4 mutations contribute to multiple developmental diseases and tumorigenesis. Here the authors describe how a highly oncogenic RECQ4 mutation alters the control of DNA synthesis, leading to abnormal DNA content and cell growth.
- Xiaohua Xu
- , Chou-Wei Chang
- & Yilun Liu
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Article
| Open AccessA covalent BTK ternary complex compatible with targeted protein degradation
Bridging covalent ligand discovery with chimeric degrader design has emerged as a mechanism to target proteins that lack enzymatic activity or are intractable. Here, the authors use biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton’s tyrosine kinase.
- James Schiemer
- , Andrew Maxwell
- & Matthew F. Calabrese
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Article
| Open AccessThe AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
Tau aggregates are associated with several neurodegenerative disorders. In this work, I. Saha and colleagues show that valosin-containing protein (VCP) recruited to Tau fibrils disaggregates them. However, this process comes at a cost: it generates seeding-active Tau species as byproduct.
- Itika Saha
- , Patricia Yuste-Checa
- & Mark S. Hipp
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Article
| Open AccessSPRTN patient variants cause global-genome DNA-protein crosslink repair defects
DNA-protein crosslinks (DPCs) are toxic DNA lesions which threaten genome stability. Here, the authors develop a method to track the fate of DPCs in cells and identify a role for the SPRTN protease in replication-independent DPC repair.
- Pedro Weickert
- , Hao-Yi Li
- & Julian Stingele
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Article
| Open AccessUSP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity
Oncogene-induced senescence (OIS) occurs in premalignant lung adenomas, but infrequently in malignant adenocarcinomas. Here the authors show that USP5-Beclin 1 axis overcomes OIS in Kras-driven lung cancer by enhancing MDM2-mediated p53 degradation.
- Juan Li
- , Yang Wang
- & Zhi-Xiong Jim Xiao
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Article
| Open AccessA widely distributed family of eukaryotic and bacterial deubiquitinases related to herpesviral large tegument proteins
The authors describe the VTD-deubiquitinases, a new eukaryotic enzyme family that is distantly related to herpesviral large tegument proteins. Structures of two family members with different linkage preferences allow insights into the mechanism and chain-specificity of this unusual deubiquitinase class.
- Ilka Erven
- , Elena Abraham
- & Kay Hofmann
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Article
| Open AccessCRL2ZER1/ZYG11B recognizes small N-terminal residues for degradation
N-degron pathways play an important role in maintaining protein homeostasis. Here, Li et al. demonstrates an additional non-Ac/N-degron pathway, in which N-terminal non-acetylated small residue degrons (Ser, Ala, or Cys) are recognized by CRL2ZER1/ZYG11B and targeted for protein degradation.
- Yao Li
- , Yueling Zhao
- & Wenyi Mi
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Article
| Open AccessConserved degronome features governing quality control associated proteolysis
How misfolded proteins are selected by the ubiquitin-conjugating system for elimination is largely unknown. Here, the authors identify conserved features of proteome-derived degradation signals, including amino acid and structural preferences, that trigger quality-control-associated proteolysis.
- Bayan Mashahreh
- , Shir Armony
- & Tommer Ravid
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Article
| Open AccessStructure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores
Proteasomes are vital eukaryotic complexes that recycle unneeded proteins. Here, the authors present the structure of a compacted proteasome derived from the dormant stage of parasitic microsporidia and bound by an endogenous inhibitory protein.
- Nathan Jespersen
- , Kai Ehrenbolger
- & Jonas Barandun
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Article
| Open AccessThe assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent proteolysis
Here the authors show the assembly/disassembly of mammalian SWI/SNF complexes is dynamically regulated by a lysine methylation mechanism involving the demethylase LSD1 and the methyl-lysine reader L3MBTL3, which recognizes SET7-methylated lysines in SMARCC1 and SMARCC2 to target them for CRL4 ubiquitin ligase-mediated proteolysis.
- Pengfei Guo
- , Nam Hoang
- & Hui Zhang
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Article
| Open AccessCooperative assembly of p97 complexes involved in replication termination
This study describes how p97Ufd1-Npl4 and the UBA-UBX protein Ubxn7 disassemble vertebrate replisomes during replication termination, and it provides novel insights into how p97 complexes assemble with UBA-UBX proteins on ubiquitylated substrates
- Olga V. Kochenova
- , Sirisha Mukkavalli
- & Johannes C. Walter
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Article
| Open AccessUbiquitin proteolysis of a CDK-related kinase regulates titan cell formation and virulence in the fungal pathogen Cryptococcus neoformans
The pathogenic yeast Cryptococcus neoformans forms large, so-called ‘titan cells’ during infection. Here, Cao et al. show that a ubiquitin ligase inhibits this process by targeting for degradation a CDK-related kinase that stimulates titan cell formation.
- Chengjun Cao
- , Keyi Wang
- & Chaoyang Xue
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Article
| Open AccessSpatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics
Methods to assess organellar content are important. Here, Park et al develop a method for rapid isolation of early/sorting endosomes and demonstrate the application of the approach for analysis of endosomal proteomes and lipidomes, and for analysis of APP processing to Aβ via β and γ-Secretases.
- Hankum Park
- , Frances V. Hundley
- & J. Wade Harper
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Article
| Open AccessA selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Protein degraders are an emerging drug modality; however, their properties lie beyond typical drug-like space. Here the authors report optimisation via structure-based exit vector and linker design towards the VHL-recruiting PROTAC ACBI2, an orally bioavailable and selective degrader of SMARCA2.
- Christiane Kofink
- , Nicole Trainor
- & William Farnaby
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Article
| Open AccessPredicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry
The formation of ternary degrader-protein complexes is a key step in the targeted degradation of proteins of interest. Here, the authors explore the structure and dynamics of such complexes applying high-performance computer simulations augmented with experimental data.
- Tom Dixon
- , Derek MacPherson
- & Jesus A. Izaguirre
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Article
| Open AccessThermosensation in Caenorhabditis elegans is linked to ubiquitin-dependent protein turnover via insulin and calcineurin signalling
Sensation of environmental changes is vital for organismal homeostasis. Here, the authors report that protein degradation in the gut of Caenorhabditis elegans is regulated through insulin and calcineurin signalling upon neuronal sensation of temperature changes.
- Alexandra Segref
- , Kavya L. Vakkayil
- & Thorsten Hoppe
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Article
| Open AccessStructure of the PAPP-ABP5 complex reveals mechanism of substrate recognition
PAPP-A substrate selectivity underlies the tight regulation of IGF signaling. Here, the authors report cryo-EM structures of dimeric PAPP-A in its substrate-free form and in complex with a peptide substrate, which combined with biochemical assays provide a mechanism for PAPP-A substrate binding and selectivity.
- Russell A. Judge
- , Janani Sridar
- & Qi Hao
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Article
| Open AccessHighly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence
Dynamic regulation of cellular proteostasis is linked to the metabolic state of quiescent cells in vivo. Here, the authors show, in multiple organisms, that shifts in the ubiquitin-proteome system are coupled to mitochondrial metabolic changes and subsequent respiratory quiescence.
- Sibiao Yue
- , Lei Wang
- & Matthew H. Sieber
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Article
| Open AccessRegulation of AUXIN RESPONSE FACTOR condensation and nucleo-cytoplasmic partitioning
Auxin-driven transcriptional responses are mediated by ARF transcription factors. Here the authors characterize an F-box protein, AFF1, that regulates the accumulation, condensation, and nucleo-cytoplasmic partitioning of ARF19 and ARF7.
- Hongwei Jing
- , David A. Korasick
- & Lucia C. Strader
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Article
| Open AccessEfferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity
Efficient removal of apoptotic cells by phagocytosis underlies tissue development, wound repair, host defense and organ homeostasis. Here, authors identify TRPM7 as a regulator of cargo acidification and Ca2+ signaling during apoptotic cell clearance.
- Michael S. Schappe
- , Marta E. Stremska
- & Bimal N. Desai
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Article
| Open AccessStress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate
While cellular stress shuts down translation, how protein degradation occurs with stress is incompletely understood. The authors describe a stress-induced phase separated organelle that mediates ubiquitin-independent degradation in the proteasome.
- Daniel C. Carrettiero
- , Maria C. Almeida
- & Kenneth S. Kosik
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Article
| Open AccessCryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation
The GID E3 ligase regulates glucose-induced degradation in yeast, and key physiology. This study unveils E3 ligase regulation by reshaping the substrate binding site, blocking substrate access to ubiquitination active sites, and a Cage-like assembly.
- Shuai Qiao
- , Chia-Wei Lee
- & Brenda A. Schulman
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Article
| Open AccessInsights into the client protein release mechanism of the ATP-independent chaperone Spy
How ATP-independent chaperones release their clients without energy input remains enigmatic. Here the authors discover that chaperone Spy uses its long, disordered N terminus to facilitate client release through competitive, dynamic intramolecular interactions with Spy’s client binding surface.
- Wei He
- , Xinming Li
- & Shu Quan
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Article
| Open AccessDevelopment of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms
t ag-T argetedP roteinD egrader (tTPD) systems are powerful tools for preclinical target validation. Here the authors extend the tTPD platform by developing NanoTACs that degrade NanoLuc tagged substrates and benchmark each tTPD system using an interchangeable tag reporter system.- Christoph Grohmann
- , Charlene M. Magtoto
- & Rebecca Feltham
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Article
| Open AccessUSP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer
The biological roles of deubiquitinating enzymes (DUBs) in pancreatic ductal adenocarcinoma (PDAC) are not fully explored. Here the authors perform activity based proteomics with a loss of function genetic screen and identify that USP25 promotes PDAC growth and survival through HIF-1 protein stability and transcriptional activity.
- Jessica K. Nelson
- , May Zaw Thin
- & Axel Behrens
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Article
| Open AccessProteolysis of adaptor protein Mmr1 during budding is necessary for mitochondrial homeostasis in Saccharomyces cerevisiae
Mitochondria are transported to daughter cells by myosin via an adaptor protein Mmr1 during budding in yeast. Here they show that the regulated proteolysis of Mmr1 after mitochondria inheritance is required for mitochondrial homeostasis.
- Keisuke Obara
- , Taku Yoshikawa
- & Takumi Kamura
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Article
| Open AccessPhagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
- Torben Mentrup
- , Anna Yamina Stumpff-Niggemann
- & Bernd Schröder
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Article
| Open AccessStructural basis for the mechanisms of human presequence protease conformational switch and substrate recognition
Presequence protease (PreP) is essential to mitochondrial proteostasis. This study leverages advanced vitrification techniques to solve cryoEM structures of apo- and substrate-bound PreP and integrates these data with other analysis to reveal key stages and mechanistic insights of the PreP catalytic cycle.
- Wenguang G. Liang
- , Juwina Wijaya
- & Wei-Jen Tang
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Article
| Open AccessUBR4/POE facilitates secretory trafficking to maintain circadian clock synchrony
Although ubiquitin ligases are known to control clock protein degradation, their other roles in clock neurons are unclear. Here the authors report that UBR4 promotes export of neuropeptides from the Golgi for axonal trafficking, which is important for circadian clock synchrony in mice and flies.
- Sara Hegazi
- , Arthur H. Cheng
- & Hai-Ying Mary Cheng
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Article
| Open AccessThe YΦ motif defines the structure-activity relationships of human 20S proteasome activators
The proteasome complexes, composed of 20S core particles and one or two regulatory particles (proteasome activators), degrade most eukaryotic proteins. Here, the authors identify a sequence motif and resolve its interactions mediating the activation of the human 20S proteasome.
- Kwadwo A. Opoku-Nsiah
- , Andres H. de la Pena
- & Jason E. Gestwicki
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Article
| Open AccessUbiquitin and a charged loop regulate the ubiquitin E3 ligase activity of Ark2C
Attachment of ubiquitin to proteins is tightly regulated and controls many signalling pathways. Here, the authors show that addition of ubiquitin by the RING E3 ligases Arkadia and Ark2C is enhanced by ubiquitin and a charged loop that precedes the RING domain.
- Andrej Paluda
- , Adam J. Middleton
- & Catherine L. Day
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Article
| Open AccessThe AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
Targeted protein degradation is a promising approach for basic research and therapeutic applications. Here, the authors develop a targeted protein degradation platform called AUTOTAC to degrade oncoproteins and neurodegeneration-associated proteins via the p62-dependent autophagy-lysosome system.
- Chang Hoon Ji
- , Hee Yeon Kim
- & Yong Tae Kwon
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Article
| Open AccessAllosteric control of Ubp6 and the proteasome via a bidirectional switch
The interplay of the proteasome and deubiquitinase Ubp6 is crucial for the degradation of ubiquitylated substrates. Here, the authors provide structural insights into the allosteric mechanism by which the activities of both Ubp6 and the proteasome are regulated.
- Ka Ying Sharon Hung
- , Sven Klumpe
- & Daniel Finley
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Article
| Open AccessCotranslational N-degron masking by acetylation promotes proteome stability in plants
N-terminal protein acetylation is required for plant viability. Here the authors show that reducing N-terminal acetylation by NatA leads to an increase in global protein turnover that is facilitated by absent masking of a novel N-degron
- Eric Linster
- , Francy L. Forero Ruiz
- & Markus Wirtz
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Article
| Open AccessStructure of Vibrio collagenase VhaC provides insight into the mechanism of bacterial collagenolysis
The collagenolytic mechanism of Vibrio collagenase, a virulence factor, remains unclear. Here, the authors report the structure of Vibrio collagenase VhaC and propose the mechanism for collagen recognition and degradation, providing new insight into bacterial collagenolysis.
- Yan Wang
- , Peng Wang
- & Yu-Zhong Zhang
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Article
| Open AccessStructural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex
Pup is the bacterial analog of ubiquitin for targeting proteins to the proteasome. Here, the authors use cryoEM to visualize structures of the Mycobacterium tuberculosis proteasome translocating a Pup-tagged substrate.
- Mikhail Kavalchuk
- , Ahmad Jomaa
- & Eilika Weber-Ban
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Article
| Open AccessLinking post-translational modifications and protein turnover by site-resolved protein turnover profiling
Post-translational modifications (PTMs) can regulate cellular protein function but their global impact on protein turnover is largely unknown. Here, the authors develop proteomic workflows to profile PTM-resolved protein turnover and analyze the effects of phosphorylation, acetylation and ubiquitination.
- Jana Zecha
- , Wassim Gabriel
- & Bernhard Kuster
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Article
| Open AccessPlasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis
ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.
- Ivana Slamova
- , Rozita Adib
- & J. Paul Simons
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Article
| Open AccessStructural basis for the E3 ligase activity enhancement of yeast Nse2 by SUMO-interacting motifs
Nse2 is a SUMO E3 ligase component of the Smc5/6 multisubunit complex involved in the DNA repair and chromosome integrity. Here, the structure of the Nse2 in complex with an E2-SUMO thioester mimetic reveals the combined action of two SIM motifs during the E3- dependent conjugation reaction.
- Nathalia Varejão
- , Jara Lascorz
- & David Reverter
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Article
| Open AccessThe NUCKS1-SKP2-p21/p27 axis controls S phase entry
Entry into S phase of the cell cycle is regulated positively by mitogens and negatively by DNA damage; however, how balance of these signals is achieved is not well known. Here the authors show that the NUCKS1-SKP2- p21/p27 axis integrates this information, where the NUCKS1 transcription factor affects levels of p21/p27 to readout the mitogen:DNA damage balance and regulate S phase entry decision.
- Samuel Hume
- , Claudia P. Grou
- & Grigory L. Dianov
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Article
| Open AccessDevelopment of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
Simultaneous targeting of BCL-xL and BCL-2 is an attractive approach for cancer treatment. Based on information gained by computational structure modelling, the authors develop a PROTAC that induces degradation of both BCL-xL and BCL-2 and effectively targets BCL-xL/2-dependent leukaemia cells.
- Dongwen Lv
- , Pratik Pal
- & Daohong Zhou
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Article
| Open AccessIdentification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis
UBE3A gene dysregulation is associated with neurodevelopmental disorders, but predicting the function of UBE3A variants remains difficult. The authors use a high-throughput assay to categorize variants by functional activity, and show that UBE3A hyperactivity increases the risk of neurodevelopmental disease.
- Kellan P. Weston
- , Xiaoyi Gao
- & Jason J. Yi
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Article
| Open AccessGenetic fusions favor tumorigenesis through degron loss in oncogenes
The impact of genetic fusions on degrons, which are motifs for ubiquitin-mediated protein degradation, has not been fully explored. Here, the authors analyse fusion genes affecting degrons in pan-cancer genomics data, validate their functional impact and find enrichment for both internal and C-terminal degron losses.
- Jing Liu
- , Collin Tokheim
- & Wenyi Wei
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Article
| Open AccessG3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer
SPOP functions as a tumour suppressor in prostate cancer but how the protein is regulated is unclear. Here, the authors identify G3BP1 as a competitive inhibitor of SPOP and show that G3BP1-SPOP axis activates androgen signalling to drive tumorigenesis.
- Chandrani Mukhopadhyay
- , Chenyi Yang
- & Pengbo Zhou
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Article
| Open AccessMapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation
Accumulation of advanced glycation end products such as carboxymethyllysine (CML) has been associated with aging but their molecular roles are largely unclear. Here, the authors use proteomics to identify CML sites and show that CML formation affects protein homeostasis and cell proliferation.
- Simone Di Sanzo
- , Katrin Spengler
- & Regine Heller
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Article
| Open AccessCompetitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
SOX2 is required for the maintenance of glioblastoma stem cells (GSCs). Here the authors identify that the RING family E3 ubiquitin ligase TRIM26 promotes SOX2 stability in a non-canonical ligase-independent manner and thus, increases the tumorigenicity of GSCs.
- Tatenda Mahlokozera
- , Bhuvic Patel
- & Albert H. Kim
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Article
| Open AccessThe 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag
The 20S particle is part of the 26S proteasome, but also exists as a free complex. Here, the authors outline signature activities of the 20S and combine chemical, structural, functional and proteomic assays to show that the 20S can degrade ubiquitin tags along with conjugated substrates.
- Indrajit Sahu
- , Sachitanand M. Mali
- & Michael H. Glickman