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The 26S proteasome is assembled in several steps, however the extent to which this assembly occurs before or after transport into the nucleus remains unclear. Pack et al.show that full assembly can occur in the cytoplasm, and that a concatameric form of the fully assembled complex is a substrate for nuclear import.

Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.

The Lys48-linked polyubiquitin-mediated proteasomal degradation in yeast depends on Cdc48 and its cofactors Ufd1 and Npl4. Here, the authors present crystal structures of Npl4 bound to Lys48-linked diubiquitin and the Npl4-binding motif of Ufd1, providing insights into the reaction mechanism of the Cdc48- Ufd1/Npl4 complex.

Motor neurons degenerate in amyotrophic lateral sclerosis (ALS), but the cellular basis of their selective vulnerability remains elusive. Here, the authors show that large motor neurons experience excess degradation stress, implicating catabolic burden as a potential therapeutic and preventive target.

Living cells must do away with regulatory proteins that are not needed. News comes of a considerable advance in understanding how the main agent of destruction, the proteasome, catches its targets.

The structure of zebrafish DUB USP30 in complex with a Lys6-linked diUb, along with biochemistry analyses, reveals the basis for Lys6-linkage specificity.

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.

Targeted protein degradation harnessing the ubiquitin system is a groundbreaking modality in drug discovery. Here, the authors identify cellular signaling pathways, such as PARG, PERK, or HSP90, that modulate the targeted degradation of the anticancer targets such as BRD4 induced by PROTACs.

The ubiquitin conjugation system regulates the canonical NF-κB-activation pathway, which mediates immune responses. Linear polyubiquitin chains—in which the C-terminal glycine of ubiquitin is conjugated to the α-amino group of the amino-terminal methionine of another ubiquitin—are generated by a unique ubiquitin ligase complex called linear ubiquitin chain assembly complex (LUBAC) composed of two RING domain proteins called HOIL-1 and HOIP. This is one of three complementary studies identifying a novel component of the LUBAC complex called SHARPIN, which is recruited to receptor signalling complexes (RSCs) that form after TNF and CD40L stimulation. The LUBAC complex containing SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo and is required for the activation of NF-κB signalling.

Hyperosmotic stress leads to a phase separation of the proteasome, triggered by interactions between RAD23B and ubiquitylated proteins, which bring together p97 and proteasome-associated proteins into nuclear proteolytic foci.

Heterobifunctional small degrader molecules that tether endogenous E3 ubiquitin ligases are promising substrates for targeted protein degradation, however, the precise formation of the E3 ligase–target complex remains challenging and limits their application. Here, the authors introduce indirect ubiquitination of the target proteins via non-covalent interactions that bypass E3 ligases, enabling efficient protein degradation.

Ubiquitylation is a dynamic post-translational modification involved in the regulation of numerous cellular processes. Here the authors describe Ub-ProT: a method to measure the length of substrate-attached ubiquitin chains in biological samples, and demonstrate a critical role for chain length in directing substrates to specific cellular pathways.

Phosphorylation of insulin receptor substrate (IRS)-1/2 by insulin-like growth factor (IGF)-I receptor tyrosine kinase is essential for IGF signalling. Here, the authors show that monoubiquitination of IRS-2 by the ubiquitin ligase Nedd4 recruits IRS-2 to the cell membrane and increases IRS-2 phosphorylation and IGF signalling.

Ubiquitin is a stable and soluble protein, but it is commonly found in inclusion bodies in neurodegenerative disorders and cancer. Here, Morimoto et al. report that increasing ubiquitin chain length leads to the formation of amyloid-like fibrils, which are degraded by an autophagy mechanism.

Akizuki et al. reveal an unexpected role for K63-linked ubiquitin chains and the E2 enzyme UBE2N in degrader-induced degradation of cIAP1 through the proteasome, demonstrating the diversity of the ubiquitin code used for targeted degradation.

Ubiquitylation of histone H3 (H3Ub2) by UHRF1 recruits DNMT1 to chromatin, which is essential for DNA methylation inheritance. Here, the authors provide evidence that there are two distinct mechanisms underlying replication timing-dependent recruitment of DNMT1 through PAF15Ub2 and H3Ub2, both of which are required for high fidelity DNA methylation inheritance.

Identification of SDD1 mRNA from Saccharomyces cerevisiae as an endogenous RQC substrate allows analysis of the mechanism underlying translational stalling and Hel2-dependent polyubiquitination of collided ribosomes to provide insight into ribosome dissociation.

Fuseya et al. show that HOIL-1L catalyses monoubiquitination on all three LUBAC subunits, thereby impairing the function of LUBAC and its role in infection defence and dermatitis pathogenesis.

NF-κB signalling protein NEMO is the first physiological substrate for linear head-to-tail polyubiquitin chains. The heterodimeric ubiquitin ligase LUBAC catalyses the reaction and mice lacking a LUBAC subunit show defects in NF-κB signalling.

Ubiquitin, known for its role in post-translational modification of other proteins, undergoes post-translational modification itself; after a decrease in mitochondrial membrane potential, the kinase enzyme PINK1 phosphorylates ubiquitin at Ser 65, and the phosphorylated ubiquitin then interacts with ubiquitin ligase (E3) enzyme parkin, which is also phosphorylated by PINK1, and this process is sufficient for full activation of parkin enzymatic activity.

Martin Reincke, Martin Fassnacht and colleagues identify somatic mutations in the USP8 deubiquitinase gene in corticotroph adenomas in Cushing's disease. The mutations enhanced proteolytic cleavage and catalytic activity of USP8, which led to activation of EGF receptor signaling.

Several protein quality control mechanisms are in place to trigger the rapid degradation of aberrant polypeptides and mRNAs. Here the authors describe a mechanism of ribosome-mediated quality control that involves the ubiquitination of ribosomal proteins by the E3 ubiquitin ligase Hel2/RQT1.

Daisuke Oikawa et al. provide structural insights into how small-molecule inhibitors of LUBAC ubiquitin ligase, HOIPINs, bind to LUBAC. They find that HOIPINs trigger apoptosis in lymphoma cells and alleviate psoriasis in mice, suggesting the potential therapeutic utility of HOIPINs.

Nakabayashi et al find that the E3 ligase MIB2 ubiquitylates the apoptosis-inhibitor cFLIP and that deletion of MIB2 enhances both RIPK1 kinase-dependent and -independent apoptosis through an increase in RIPK1 kinase activity and impairment of ubiquitylation of cFLIP_L, respectively.

Watanabe et al. combine two previously developed strategies to identify E3 ubiquitin ligase substrates into a method, TR-TUBE that is subsequently used to identify substrates of the Parkin and TRIM28 ligases. They identify known substrates, validating the utility of the approach, and find that TRIM28 targets Cyclin A and TFIIB for degradation.