TRIM21-mediated ubiquitination of SQSTM1/p62 abolishes its Ser403 phosphorylation and enhances palmitic acid cytotoxicity.

Long-chain free fatty acids (FFAs) accumulation and oxidative toxicity is a major cause for several pathological conditions. The mechanisms underlying FFA cytotoxicity remain elusive. Here we show that palmitic acid (PA), the most abundant FFA in the circulation, induces S403 phosphorylation of SQSTM1/p62 (sequestosome 1) and its aggregation, which sequesters KEAP1 and activates the non-canonical SQSTM1-KEAP1-NFE2L2 antioxidant pathway.

Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages.

Jumbo phages are a group of tailed bacteriophages with large genomes and capsids. As a prototype of jumbo phage, ΦKZ infects Pseudomonas aeruginosa, a multi-drug-resistant (MDR) opportunistic pathogen leading to acute or chronic infection in immunocompromised individuals. It holds potential to be used as an antimicrobial agent and as a model for uncovering basic phage biology.

CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity.

Protein aggregation caused by the disruption of proteostasis will lead to cellular cytotoxicity and even cell death, which is implicated in multiple neurodegenerative diseases. The elimination of aggregated proteins is mediated by selective macroautophagy receptors, which is termed aggrephagy. However, the identity and redundancy of aggrephagy receptors in recognizing substrates remain largely unexplored.

PACT inhibits the replication of SARS-CoV-2 through the blockage of GSK-3β-N-nsp3 cascade.

The protein activator of protein kinase R (PKR) (PACT) has been shown to play a crucial role in stimulating the host antiviral response through the activation of PKR, retinoic acid-inducible gene I, and melanoma differentiation-associated protein 5. Whether PACT can inhibit viral replication independent of known mechanisms is still unrevealed. In this study, we show that, like many viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks GSK-3β to facilitate its replication.

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S.

SARS-CoV-2 NSP7 inhibits type I and III IFN production by targeting the RIG-I/MDA5, TRIF, and STING signaling pathways.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS-CoV-2 NSP7 inhibited the production of type I and III interferons (IFNs) by targeting the RIG-I/MDA5, Toll-like receptor (TLR3)-TRIF, and cGAS-STING signaling pathways. SARS-CoV-2 NSP7 suppressed the expression of IFNs and IFN-stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS-CoV-2 virus-like particles.

Genome-Wide Analysis of the Indispensable Role of Non-structural Proteins in the Replication of SARS-CoV-2.

Understanding the process of replication and transcription of SARS-CoV-2 is essential for antiviral strategy development. The replicase polyprotein is indispensable for viral replication. However, whether all nsps derived from the replicase polyprotein of SARS-CoV-2 are indispensable is not fully understood.

Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy.

Immune checkpoint blockade therapy has drastically improved the prognosis of certain advanced-stage cancers. However, low response rates and immune-related adverse events remain important limitations. Here, we report that inhibiting ALG3, an a-1,3-mannosyltransferase involved in protein glycosylation in the endoplasmic reticulum (ER), can boost the response of tumors to immune checkpoint blockade therapy.

ORF8 protein of SARS-CoV-2 reduces male fertility in mice.

As one of the most rapidly evolving proteins of the genus Betacoronavirus, open reading frames (ORF8's) function and potential pathological consequence in vivo are still obscure. In this study, we show that the secretion of ORF8 is dependent on its N-terminal signal peptide sequence and can be inhibited by reactive oxygen species scavenger and endoplasmic reticulum-Golgi transportation inhibitor in cultured cells. To trace the effect of its possible in vivo secretion, we examined the plasma samples of coronavirus disease 2019 (COVID-19) convalescent patients and found that the patients aged from 40 to 60 had higher antibody titers than those under 40.

Event-Triggered Distributed Average Tracking Control for Lipschitz-Type Nonlinear Multiagent Systems.

This article investigates the event-triggered distributed average tracking (ETDAT) control problems for the Lipschitz-type nonlinear multiagent systems with bounded time-varying reference signals. By using the state-dependent gain design approach and event-triggered mechanism, two types of ETDAT algorithms called: 1) static and 2) adaptive-gain ETDAT algorithms are developed. It is the first time to introduce the event-triggered strategy into DAT control algorithms and investigate the ETDAT problem for multiagent systems with Lipschitz nonlinearities, which is more practical in real physical systems and can better meet the needs of practical engineering applications.

Reverse genetics systems for SARS-CoV-2.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) has caused severe public health crises and heavy economic losses. Limited knowledge about this deadly virus impairs our capacity to set up a toolkit against it. Thus, more studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology are urgently needed.

Inhibition of SARS-CoV-2 replication by zinc gluconate in combination with hinokitiol.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic is currently the major challenge to global public health. Two proteases, papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro or Mpro), are indispensable for SARS-CoV-2 replication, making them attractive targets for antiviral therapy development. Here we screened a panel of essential metal ions using a proteolytic assay and identified that zinc gluconate, a widely-used zinc supplement, strongly inhibited the proteolytic activities of the two proteases in vitro.

Oxidative stress transforms 3CLpro into an insoluble and more active form to promote SARS-CoV-2 replication.

3CLpro is a key proteinase for SARS-CoV-2 replication and serves as an important target for antiviral drug development. However, how its activity is regulated intracellularly is still obscure. In this study, we developed a 3CLpro protease activity reporter system to examine the impact of various factors, including nutrient supplements, ions, pHs, or oxidative stress inducers, on 3CLpro protease activity.

Allosteric inhibition of SARS-CoV-2 3CL protease by colloidal bismuth subcitrate.

The SARS-CoV-2 3-chymotrypsin-like protease (3CLpro or Mpro) is a key cysteine protease for viral replication and transcription, making it an attractive target for antiviral therapies to combat the COVID-19 disease. Here, we demonstrate that bismuth drug colloidal bismuth subcitrate (CBS) is a potent inhibitor for 3CLpro and . Rather than targeting the cysteine residue at the catalytic site, CBS binds to an allosteric site and results in dissociation of the 3CLpro dimer and proteolytic dysfunction.

Altered gut microbiome in FUT2 loss-of-function mutants in support of personalized medicine for inflammatory bowel diseases.

The FUT2 loss-of-function mutations are highly prevalent and are associated with inflammatory bowel disease (IBD). To investigate the impact of FUT2 loss-of-function mutation on the gut microbiota in patients with IBD, 81 endoscopically confirmed IBD patients were genotyped and divided into 3 groups: homozygous for functional FUT2 genes (SeSe), with one copy of non-functional FUT2 gene (Sese), or homozygous for non-functional FUT2 genes (sese). Escherichia, which attaches to fucosylated glycoconjugates, was the only abundant genus exhibiting decreased abundance in sese patients.

Genome-wide analysis of protein-protein interactions and involvement of viral proteins in SARS-CoV-2 replication.

Background: Analysis of viral protein-protein interactions is an essential step to uncover the viral protein functions and the molecular mechanism for the assembly of a viral protein complex. We employed a mammalian two-hybrid system to screen all the viral proteins of SARS-CoV-2 for the protein-protein interactions.

Results: Our study detected 48 interactions, 14 of which were firstly reported here.

Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin.

Background: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway.

ISL2 modulates angiogenesis through transcriptional regulation of ANGPT2 to promote cell proliferation and malignant transformation in oligodendroglioma.

Oligodendroglioma is an important type of lower-grade glioma (LGG), which is a slowly progressing brain tumor. Many LGGs eventually transform into a more aggressive or malignant type. Enhanced angiogenesis is a characteristic of malignantly transformed oligodendroglioma (m-oligodendroglioma).

A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection.

Autophagy is a conserved process that delivers cytosolic substances to the lysosome for degradation, but its direct role in the regulation of antiviral innate immunity remains poorly understood. Here, through high-throughput screening, we discovered that CCDC50 functions as a previously unknown autophagy receptor that negatively regulates the type I interferon (IFN) signaling pathway initiated by RIG-I-like receptors (RLRs), the sensors for RNA viruses. The expression of CCDC50 is enhanced by viral infection, and CCDC50 specifically recognizes K63-polyubiquitinated RLRs, thus delivering the activated RIG-I/MDA5 for autophagic degradation.

Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism.

Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer.

Involvement of acid-sensing ion channel 1a in gastric carcinoma cell migration and invasion.

Acidic microenvironment, particularly acid-sensing ion channel 1a (ASIC1a), has been reported to promote carcinoma cell proliferation as well as migration. In this study, we explored the effect of ASIC1a on migration and invasion of gastric carcinoma (GC). ASIC1a expression levels were examined in paired GC and adjacent normal tissues from 16 patients by immunohistochemistry.