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The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions. A selective and potent CDK2 degrader was developed that induced differentiation of acute myeloid leukemia cell lines and primary patient cells.

The tripartite motif-containing protein 21 (TRIM21) plays important roles in autophagy and innate immunity. Here, we found that HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5), as an interferon-stimulated gene 15 (ISG15) E3 ligase, catalyzes the ISGylation of TRIM21 at the Lys260 and Lys279 residues. Moreover, IFN- β also induces TRIM21 ISGylation at multiple lysine residues, thereby enhancing its E3 ligase activity for K63-linkage-specific ubiquitination and resulting in increased levels of TRIM21 and p62 K63-linked ubiquitination. The K63-linked ubiquitination of p62 at Lys7 prevents its self-oligomerization and targeting to the autophagosome. Taken together, our study suggests that the ISGylation of TRIM21 plays a vital role in regulating self-oligomerization and localization of p62 in the autophagy induced by IFN- β .

Dissection of the physiological interactomes of histone post-translational modifications (hPTMs) is crucial for understanding epigenetic regulatory pathways. Peptide- or protein-based histone photoaffinity tools expanded the ability to probe the epigenetic interactome, but in situ profiling in native cells remains challenging. Here, we develop a nucleus-targeting histone-tail-based photoaffinity probe capable of profiling the hPTM-mediated interactomes in native cells, by integrating cell-permeable and nuclear localization peptide modules into an hPTM peptide equipped with a photoreactive moiety. These types of probes, such as histone H3 lysine 4 trimethylation and histone H3 Lysine 9 crotonylation probes, enable the probing of epigenetic interactomes both in HeLa cell and hard-to-transfect RAW264.7 cells, resulting in the discovery of distinct interactors in different cell lines. The utility of this probe is further exemplified by characterizing interactome of emerging hPTM, such as AF9 was detected as a binder of histone H3 Lysine 9 lactylation, thus expanding the toolbox for profiling of hPTM-mediated PPIs in live cells. Dissection of the physiological interactomes of histone post-translational modifications is crucial for understanding epigenetic regulatory pathways. Here, authors develop a nucleus-targeting histone-tail-based photoaffinity probe capable of profiling the hPTM-mediated interactomes in native cells.

Hepatitis E virus (HEV) is one of the main pathogenic agents of acute hepatitis in the world. The mechanism of HEV replication, especially host factors governing HEV replication is still not clear. Here, using HEV ORF1 trans -complementation cell culture system and HEV replicon system, combining with stable isotope labelling with amino acids in cell culture (SILAC) and mass spectrometry (MS), we aimed to identify the host factors regulating HEV replication. We identified a diversity of host factors associated with HEV ORF1 protein, which were putatively responsible for viral genomic RNA replication, in these two cell culture models. Of note, the protein arginine methyltransferase 5 (PRMT5)/WDR77 complex was identified in both cell culture models as the top hit. Furthermore, we demonstrated that PRMT5 and WDR77 can specifically inhibit HEV replication, but not other viruses such as HCV or SARS-CoV-2, and this inhibition is conserved among different HEV strains and genotypes. Mechanistically, PRMT5/WDR77 can catalyse methylation of ORF1 on its R458, impairing its replicase activity, and virus bearing R458K mutation in ORF1 relieves the restriction of PRMT5/WDR77 accordingly. Taken together, our study promotes more comprehensive understanding of viral infections but also provides therapeutic targets for intervention.

NKCC and KCC transporters mediate coupled transport of Na++K++Cl− and K++Cl− across the plasma membrane, thus regulating cell Cl− concentration and cell volume and playing critical roles in transepithelial salt and water transport and in neuronal excitability. The function of these transporters has been intensively studied, but a mechanistic understanding has awaited structural studies of the transporters. Here, we present the cryo-electron microscopy (cryo-EM) structures of the two neuronal cation-chloride cotransporters human NKCC1 (SLC12A2) and mouse KCC2 (SLC12A5), along with computational analysis and functional characterization. These structures highlight essential residues in ion transport and allow us to propose mechanisms by which phosphorylation regulates transport activity.Zhang et al. present the cryo-electron microscopy structures of the two neuronal cation-chloride cotransporters human NKCC1 and mouse KCC2, identifying their essential residues for ion transport. This study proposes mechanisms by which phosphorylation regulates the activity of these cation-chloride cotransporters.

Lasso peptides belong to a peculiar family of ribosomally synthesized and post-translationally modified peptides (RiPPs)—natural products with an unusual isopeptide-bonded slipknot structure. Except for assembling of this unusual lasso fold, several further post-translational modifications of lasso peptides, including C-terminal methylation, phosphorylation/poly-phosphorylation, citrullination, and acetylation, have been reported recently. However, most of their biosynthetic logic have not been elucidated except the phosphorylated paeninodin lasso peptide. Herein, we identified two novel lassomycin-like lasso peptide biosynthetic pathways and, for the first time, characterized a novel C-terminal peptide carboxyl methyltransferase involved in these pathways. Our investigations revealed that this new family of methyltransferase could specifically methylate the C terminus of precursor peptide substrates, eventually leading to lassomycin-like C-terminal methylated lasso peptides. Our studies offer another rare insight into the extraordinary strategies of chemical diversification adopted by lasso peptide biosynthetic machinery and predicated two valuable sources for methylated lasso peptide discovery.

Large tumor suppressor 1 (LATS1) is the key kinase controlling activation of Hippo signalling pathway. Post-translational modifications of LATS1 modulate its kinase activity. However, detailed mechanism underlying LATS1 stability and activation remains elusive. Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4. Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation. Mechanistically, LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation, leading to increased YAP nucleus translocation and promoted target gene expression. Functionally, LATS1-K751Q, the acetylation mimic mutant potentiated lung cancer cell migration, invasion and tumor growth, whereas LATS1-K751R, the acetylation deficient mutant inhibited these functions. Taken together, we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.

The electrocatalytic nitrogen reduction reaction (NRR) can use renewable electricity to convert water and N2 into NH3 under normal temperature and pressure conditions. However, due to the competitiveness of the hydrogen evolution reaction (HER), the ammonia production rate (RNH3) and Faraday efficiency (FE) of NRR catalysts cannot meet the needs of large-scale industrialization. Herein, by assembling hydrophobic ZIF-8 on a cerium oxide (CeO2) nanorod, we designed an excellent electrocatalyst CeO2-ZIF-8 with intrinsic NRR activity. The hydrophobic ZIF-8 surface was conducive to the efficient three-phase contact point of N2 (gas), CeO2 (solid) and electrolyte (liquid). Therefore, N2 is concentrated and H+ is deconcentrated on the CeO2-ZIF-8 electrocatalyst surface, which improves NRR and suppresses HER and finally CeO2-ZIF-8 exhibits excellent NRR performance with an RNH3 of 2.12 μg h−1 cm−2 and FE of 8.41% at −0.50 V (vs. RHE). It is worth noting that CeO2-ZIF-8 showed excellent stability in the six-cycle test, and the RNH3 and FE variation were negligible. This study paves a route for inhibiting the competitive reaction to improve the NRR catalyst activity and may provide a new strategy for NRR catalyst design.

Vitis amurensis is a wild Vitis plant that can withstand extreme cold temperatures. However, the accumulation of metabolites during cold acclimation (CA) in V . amurensis remains largely unknown. In this study, plantlets of V. amurensis and V. vinifera cv. Muscat of Hamburg were treated at 4 °C for 24 and 72 h, and changes of metabolites in leaves were detected by gas chromatography coupled with time-of-flight mass spectrometry. Most of the identified metabolites, including carbohydrates, amino acids, and organic acids, accumulated in the two types of grape after CA. Galactinol, raffinose, fructose, mannose, glycine, and ascorbate were continuously induced by cold in V. amurensis , but not in Muscat of Hamburg. Twelve metabolites, including isoleucine, valine, proline, 2-oxoglutarate, and putrescine, increased in V. amurensis during CA. More galactinol, ascorbate, 2-oxoglutarate, and putrescine, accumulated in V. amurensis , but not in Muscat of Hamburg, during CA, which may be responsible for the excellent cold tolerance in V. amurensis . The expression levels of the genes encoding β-amylase (BAMY), galactinol synthase (GolS), and raffinose synthase (RafS) were evaluated by quantitative reverse transcription-PCR. The expression BAMY ( VIT_02s0012 g00170 ) and RafS ( VIT_05s0077 g00840 ) were primarily responsible for the accumulation of maltose and raffinose, respectively. The accumulation of galactinol was attributed to different members of GolS in the two grapes. In conclusion, these results show the inherent differences in metabolites between V. amurensis and V. vinifera under CA. Grapes: staying out in the cold Studying how the wild grape Vitis amurensis copes with cold may help in breeding grape varieties that can grow at lower temperatures. To prevent frost damage, plants can increase cells’ sugar and protein contents, lowering the freezing point, and preventing ice crystal formation. V. amurensis , a wild grape native to Asia, grows well at low temperatures, but its cold-tolerance compounds have yet to be identified. Haiping Xin and Shaohua Li at the Chinese Academy of Sciences and co-workers profiled the compounds present in V. amurensis and V. vinifera cv. Muscat of Hamburg, a wine grape, following cold stress. V. amurensis cells were richer in a dozen compounds, including amino acids, organic acids, and putrescine, a component of the odor of decaying flesh. These results may help in developing grape varieties with increased cold tolerance.

A comprehensive analysis utilizing APEX2-MS and IP-MS techniques identified a total of 24 cellular targets of Vpu, three of which have been documented as restriction factors. Vpu-interacting proteins were found to be significantly enriched in pathways related to cell adhesion, RNA transport, and the spliceosome. The identification of RBM10 as a novel regulator of HIV-1 replication and infectivity, and RBM10 regulated transcription of both viral and host RNA transcripts. Vpu interacted with RBM10 and promoted its degradation through the ubiquitin-proteasome pathway.