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DUBs regulate key cellular processes, but selective tools are scarce. Here, the authors developed PROTACs for the DUB USP7, comparing degraders with inhibitors. The study provides a valuable toolbox for studying DUB functions and underscores the power of PROTACs in revealing context-specific biology.

Targeted Protein Degradation (TPD) relies on the binding of specific targets and E3 ubiquitin-ligases to promote ubiquitination and degradation of targets by the proteasome. Here, by designing chimeras that bind the proteasome-associated factor Usp14, the authors present a generalizable TPD approach based on proteasome-dependent and E3 ligase-independent small-molecule compounds.

The replicative helicase CMG is targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP. This study describes how the de-ubiquitylating enzyme USP37 protects genome stability by preventing premature TRAIP-dependent CMG unloading when replication stress impedes timely termination.

Ubiquitination of the CMG helicase triggers replisome disassembly, ensuring genome integrity. Here, the authors show that the deubiquitinase USP37 preserves replisomes during S and G2 phase by binding and deubiquitinating CMG. USP37 is vital in cells expressing oncoproteins which dysregulate DNA replication.

Kazi et al. report the crystal structure of the mitochondrial deubiquitinase USP30, a clinical stage Parkinson’s disease drug target, in complex with a specific inhibitor. The authors delineate a framework for specific deubiquitinase inhibition.

Branched ubiquitin chains promote substrates degradation. Here, the authors describe an interplay between two ubiquitin ligases, K29-linkage-specific TRIP12 and K48-linkage specific UBR5, which assembles K29/K48 branched ubiquitin chains and facilitates degradation of deubiquitylation-protected substrates.

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.

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.

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.

Initiation is the rate limiting step of protein translation. Here the authors show that recycling of the free ribosomal 40 S subunit is regulated by the deubiquitinase OTUD6. OTUD6 deubiquitinates monoubiquitinated RPS7/eS7 to promote 40 S recycling into the preinitiation complex.

Here the authors assemble a toolkit to probe K48–K63-branched ubiquitin chain function. By identifying specific binders and deubiquitinases and engineering a specific nanobody, they reveal the importance of these chains in p97-dependent processes.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Structures of the human ubiquitin-specific protease 14 in complex with the 26S proteasome captured in the act of protein degradation provide a detailed view of the functional cycle of the USP14-regulated proteasome.

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.

Zhang et al. report that the lncRNA H19 stabilizes dystrophin by competing with the ubiquitin E3 ligase TRIM63 for association with dystrophin, thereby alleviating muscular dystrophies.

Necroptosis drives arthritis. Polykratis et al. show that the deubiquitinating enzyme A20 inhibits inflammasome-dependent arthritis development by regulating macrophage necroptosis and this function depends on its ZnF7 ubiquitin binding domain.

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.

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.

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.

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.

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.

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.

TGF-β signaling is commonly aberrantly activated in gliomas and other tumors and can exert a pro-oncogenic function. The authors identify a new mechanism for upregulation of TGF-β signaling in cancer. The deubiquitinase USP15 is shown to be able to bind the TGF-β receptor complex, counteract its degradation and potentiate its stimulation of downstream mediators. USP15 is amplified in human glioblastoma and could represent a therapeutic target, as its downregulation impairs the growth of glioblastoma cells in vivo.

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.

REST transcription factor is a master regulator of neural stem and progenitor cells, which is subjected to ubiquitylation-mediated proteasomal degradation during differentiation. In progenitor cells, degradation is inhibited by the action of the deubiquitylase enzyme HAUSP to prevent untimely neuronal differentiation.

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.

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.

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.

The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by engaging two distinct exocyst complex proteins: EXO84 to modulate autophagy and SEC5 to regulate innate immune signalling. Sablina and colleagues find that whereas ubiquitylation of RALB at K47 promotes its interaction with SEC5, the de-ubiquitylase USP33 switches RALB to the EXO84–beclin complex to promote autophagy during nutrient starvation.

Post-translational modifications regulate various signaling cascades downstream of the TCR. Knobeloch and colleagues show that the deubiquitinase USP8 is required for thymocyte development by interacting with the adaptor Gads upon TCR stimulation.

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.

Ma and colleagues show that when the EMT-associated transcription factor ZEB1 is stabilized by the ATM kinase, it interacts with the ubiquitin protease USP7 to counteract CHK1 degradation and promote DNA repair in breast cancer cells.

Electron microscopy and biochemistry analyses reveal that the deubiquitinase Ubp6, in its ubiquitin-bound form, inhibits substrate deubiquitination by Rpn11, stabilizes the proteasome in a substrate-engaged conformation and interferes with the engagement of a subsequent substrate.

Cunningham et al. characterize the ubiquitin chain linkages regulated by the opposing activities of the E3 ligase parkin and the deubiquitylation enzyme USP30 on mitochondria.

Tumor-suppressor protein CYLD cleaves linear and Lys63-linked ubiquitin chains. Structures of CYLD USP domain with Met1- and Lys63-linked diubiquitins and biochemical analyses reveal the mechanism for dual specificity and provide insight into tumor-associated mutations.

The stability of the PTEN tumour suppressor protein is regulated by polyubiquitylation. Ma and colleagues identify USP13 as an enzyme reversing polyubiquitylation of PTEN, leading to PTEN stabilization and tumour suppression.