Featured
-
-
Article
| Open Access
The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes
TDRD3 is a key interaction partner of TOP3B. Here the authors provide molecular mechanisms by which TDRD3 stabilizes TOP3B protein by recruiting the deubiquitylase USP9X. In addition, they show that TDRD3 protects cells from deleterious TOP3B linked DNA and RNA cleavage complexes.
- Sourav Saha
- , Shar-yin Naomi Huang
- & Yves Pommier
-
Article
| Open Access
Non-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
-
Article
| Open Access
USP5-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
-
Article
| Open Access
A 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
-
Article
| Open Access
USP25 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
-
Article
| Open Access
Allosteric 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
-
Article
| Open Access
VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism
Autophagy and the ubiquitin–proteasome system (UPS) are cellular quality control processes, but their coordination remains unclear. Here, the authors show that branched ubiquitination of VPS34 functions as a switch between UPS and autophagy and has an important role in lipid metabolism in the liver.
- Yu-Hsuan Chen
- , Tzu-Yu Huang
- & Ruey-Hwa Chen
-
Article
| Open Access
A deubiquitylase with an unusually high-affinity ubiquitin-binding domain from the scrub typhus pathogen Orientia tsutsugamushi
Many pathogens manipulate ubiquitin-mediated signaling to evade host cell defense. Here, the authors characterize the structure and enzymatic activity of a deubiquitylase domain from the causative pathogen of scrub typhus, providing evidence for a distinct mechanism of ubiquitin chain selectivity.
- Jason M. Berk
- , Christopher Lim
- & Mark Hochstrasser
-
Article
| Open Access
USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin
Axin is a scaffolding protein known for its role in Wnt signalling that can be marked with a variety of post-translational modifications. Here, Cong et al. demonstrate that USP7 de-ubiquinates Axin and that canonical Wnt signaling output can be increased with USP7 inhibitors.
- Lei Ji
- , Bo Lu
- & Feng Cong
-
Article
| Open Access
GIGANTEA recruits the UBP12 and UBP13 deubiquitylases to regulate accumulation of the ZTL photoreceptor complex
The daily accumulation of the ZEITLUPE (ZTL) photoreceptor/E3 ubiquitin ligase relies on a light-dependent interaction with GIGANTEA (GI). Here the authors show that GI recruits two deubiquitylases to help stabilize the ZTL-GI complex during the day and likely counterbalance the activity of ZTL.
- Chin-Mei Lee
- , Man-Wah Li
- & Joshua M. Gendron
-
Article
| Open Access
PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression
PTEN is a lipid phosphatase that functions as a dose-dependent tumor suppressor through the PI3K/AKT pathway. Here the authors describe a signaling feedback mechanism where PTEN stability is regulated through transcriptional upregulation of X-linked ubiquitin-specific protease 11 (USP11) via the PI3K/FOXO pathway.
- Mi Kyung Park
- , Yixin Yao
- & Min Sup Song
-
Article
| Open Access
Usp7 regulates Hippo pathway through deubiquitinating the transcriptional coactivator Yorkie
Hippo signaling leads to the phosphorylation of the key transcriptional effector, Yap/Yki, although how Yap/Yki stability is regulated has remained unclear. Here, Sun et al. identify HAUSP/Usp7 as a conserved and clinically relevant regulator of the Hippo pathway that increases Yap/Yki stability.
- Xiaohan Sun
- , Yan Ding
- & Zizhang Zhou
-
Article
| Open Access
A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes
The Polycomb Repressive-Deubiquitinase (PR-DUB) complex is responsible for the removal of the ubiquitin epigenetic modification from Histone 2A. Here the authors describe the structure of the Drosophila PR-DUB complex, providing new insight into its regulation and how cancer-associated mutations disrupt PR-DUB activity.
- Martina Foglizzo
- , Adam J. Middleton
- & Peter D. Mace
-
Article
| Open Access
Rpn11-mediated ubiquitin processing in an ancestral archaeal ubiquitination system
Ubiquitin modification also occurs in archaea. Here, the authors characterize an archaeal ancestral ubiquitination system, present the crystal structure of the archaeal deubiquitinase Rpn11 from Caldiarchaeum subterraneum bound to ubiquitin and provide insights into evolutionary relationships.
- Adrian C. D. Fuchs
- , Lorena Maldoner
- & Jörg Martin
-
Article
| Open Access
A family of unconventional deubiquitinases with modular chain specificity determinants
Deubiquitinating enzymes (DUBs) are essential to modulate ubiquitin signaling. While known DUBs can be grouped into six families, the authors here present biochemical and structural evidence for a seventh DUB family, defining determinants of substrate specificity for two representative enzymes.
- Thomas Hermanns
- , Christian Pichlo
- & Kay Hofmann
-
Article
| Open Access
Deubiquitinase activity is required for the proteasomal degradation of misfolded cytosolic proteins upon heat-stress
Ubiquitination of misfolded proteins usually results in protein degradation. Here, the authors show that two deubiquitinases—enzymes that remove ubiquitin—are required for the proteasomal degradation of misfolded proteins in response to heat-shock in yeast.
- Nancy N. Fang
- , Mang Zhu
- & Thibault Mayor
-
Article
| Open Access
Ubiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization
The relaying of Wnt signals to the cytoplasm requires the formation of signalosomes through the reversible polymerization of Dishevelled (Dvl). Here the authors establish the functional consequences of ubiquitination of the Dvl DIX domain and identify deubiquitinases predicted to promote Dvl polymerization.
- Julia Madrzak
- , Marc Fiedler
- & Jason W. Chin
-
Article
| Open Access
UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
- Yoko Goto
- , Lihua Zeng
- & Hiroshi Harada
-
Article
| Open Access
Screening of DUB activity and specificity by MALDI-TOF mass spectrometry
Deubiquitylases (DUBs) remove ubiquitin chains from proteins. Here the authors develop a mass spectrometry-based DUB activity screen using unmodified diubiquitin isomers to characterize substrate specificity for 42 human DUBs, and assess the potency and selectivity of 11 DUB inhibitors.
- Maria Stella Ritorto
- , Richard Ewan
- & Matthias Trost
-
Article |
The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells
Mutations in the deubiquitinase gene CYLD are associated with cylindromatosis, a disease characterized by the development of skin appendage tumours. Eguether et al.discover that CYLD localizes to centrosomes and is required for basal body migration and docking, providing insight into its tumour suppressor activity.
- Thibaut Eguether
- , Maria A. Ermolaeva
- & Anne-Marie Tassin
-
Article
| Open Access
Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells
Deubiquitinases regulate protein stability, localization and activity, and yet the mechanisms controlling their activity remain poorly understood. Lee et al. show that these enzymes are reversibly inhibited by reactive oxygen species through oxidation of catalytic cysteine residues.
- Jin-Gu Lee
- , Kheewoong Baek
- & Yihong Ye
-
Article |
Regulation of A20 and other OTU deubiquitinases by reversible oxidation
Ovarian tumour deubiquitinases are cysteine proteases that cleave polyubiquitin chains. Here the authors show that these enzymes are susceptible to reversible oxidation, and present crystal structures which reveal how the reversibly oxidized catalytic cysteine residue is stabilized by the active site.
- Yogesh Kulathu
- , Francisco J. Garcia
- & David Komander
-
Article |
Regulation of MITF stability by the USP13 deubiquitinase
MITF is a transcription factor required for melanocyte development, which is activated in some melanomas. Zhao and colleagues show that USP13 removes ubiquitin from MITF, stabilizes MITF protein levels and enhances colony formation, suggesting that USP13 may be a therapeutic target in melanoma.
- Xiansi Zhao
- , Brian Fiske
- & David E Fisher
-
Article
| Open Access
The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility
Deubiquitinating enzymes are involved in multiple cellular processes, including cell viability. The authors reveal a role for the deubiquitinating enzyme, USP17, in the migration of cells in response to chemokines and show that USP17 is required for the relocalization of GTPases involved in cell motility.
- Michelle de la Vega
- , Alyson A. Kelvin
- & James A. Johnston
Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells