TRIM72‑mediated degradation of the short form of p62/SQSTM1 rheostatically controls selective autophagy in human cells

Dear Editor,Autophagy is an evolutionarily conserved catabolic process that involves the sequestration and transport of organelles,macromolecules,or invading microorganisms to lysosomes for degradation[1].Sequestosome 1(p62/SQSTM1)was the first protein shown to bind target-associated ubiquitin(Ub)and LC3 conjugated to the phagophore membrane,thus,acting as an important autophagy receptor for ubiquitinated targets[2].

Host cyclophilin A facilitates SARS-CoV-2 infection by binding and stabilizing spike on virions

Dear Editor,The novel coronavirus SARS-CoV-2 rapidly evolutes to increase its infectivity and transmissibility,facilitates its immune escape,impairs vaccine efficacy,and currently causes repeated infections in human,which is mainly determined by the accumulated mutations in spike(S).1 Transmembrane S is a heavily glycosylated protein on the surface of the virion as homotrimer,responsible for binding to human angiotensin-converting enzyme 2(hACE2)receptor.2 While the architecture of S trimers has been well studied,how the stability of S is regulated by potential host factors remains unknown.

Coming of age:the formation and function of age-associated B cells

B cells are generated in the bone marrow during ontogeny and migrate to peripheral lymphoid organs,where they encounter antigens to elicit humoral immunity.During the past decade,many novel B-cell subsets with distinct phenotypes and functions have been identified,and among these subsets,age-associated B cells(ABCs)were first characterized as a B-cell subset that accumulates with age[1].

Distinct and relatively mild clinical characteristics of SARS-CoV-2 BA.5 infections against BA.2

Dear Editor,The global pandemic of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron variant has resulted in its continuous evolution and the emergence of numerous subvariants of Omicron(https://gisaid.org/).Currently,possibly owing to the increased evasion of neutralizing antibodies elicited by previous infection and vaccination and the higher transmissibility,the BA.5 variant has replaced BA.2 variant and dominated the pandemic.

Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases

DNA sensing and timely activation of interferon(IFN)-mediated innate immunity are crucial for the defense against DNA virus infections and the clearance of abnormal cells.However,overactivation of immune responses may lead to tissue damage and autoimmune diseases;therefore,these processes must be intricately regulated.STING is the key adaptor protein,which is activated by cyclic GMP-AMP,the second messenger derived from cGAS-mediated DNA sensing.Here,we report that CCDC50,a newly identified autophagy receptor,tunes STING-directed type I IFN signaling activity by delivering K63-polyubiquitinated STING to autolysosomes for degradation.Knockout of CCDC50 significantly increases herpes simplex virus 1(HSV-1)-or DNA ligand-induced production of type I IFN and proinflammatory cytokines.Ccdc50-deficient mice show increased production of IFN,decreased viral replication,reduced cell infiltration,and improved survival rates compared with their wild-type littermates when challenged with HSV-1.Remarkably,the expression of CCDC50 is downregulated in systemic lupus erythematosus(SLE),a chronic autoimmune disease.CCDC50 levels are negatively correlated with IFN signaling pathway activation and disease severity in human SLE patients.CCDC50 deficiency potentiates the cGAS-STING-mediated immune response triggered by SLE serum.Thus,our findings reveal the critical role of CCDC50 in the immune regulation of viral infections and autoimmune diseases and provide insights into the therapeutic implications of CCDC50 manipulation.

Virome in healthy pangolins reveals compatibility with multiple potentially zoonotic viruses

Previous studies have identified multiple viruses in dead or severely diseased pangolins,but descriptions of the virome in healthy pangolins are lacking.This poses a greater risk of cross-species transmission due to poor preventive awareness and frequent interactions with breeders.In this study,we investigated the viral composition of 34 pangolins with no signs of disease at the time of sampling and characterized a large number of arthropodassociated viruses belonging to 11 families and vertebrate viruses belonging to eight families,including those with pathogenic potential in humans and animals.Several important vertebrate viruses were identified in the pangolins,including parvovirus,pestivirus,and picobirnavirus.The picobirnavirus was clustered with human and grey teal picobirnaviruses.Viruses with cross-species transmission ability were also identified,including circovirus,rotavirus,and astrovirus.Our study revealed that pangolins are frequently exposed to arthropod-associated viruses in the wild and can carry many vertebrate viruses under natural conditions.This study provides important insights into the virome of pangolins,underscoring the importance of monitoring potential pathogens in healthy pangolins to prevent outbreaks of infectious diseases in domesticated animals and humans.

Preclinical characterization and anti-SARS-CoV-2 efficacy of ATV014:an oral cyclohexanecarboxylate prodrug of 1′-CN-4-aza-7,9-dideazaadenosine C-nucleoside

Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of the global pandemic coronavirus disease 2019(COVID-19),has proven itself to be a highly virulent respiratory pathogen with an unpredictable evolutionary capacity,posing a persistent threat to mankind.At the time of this manuscript’s publication.

Non-Structural Protein 5 of Zika Virus Interacts with p53 in Human Neural Progenitor Cells and Induces p53-Mediated Apoptosis

Zika virus(ZIKV) infection could disrupt neurogenesis and cause microcephaly in neonates by targeting neural progenitor cells(NPCs). The tumor suppressor p53-mediated cell cycle arrest and apoptotic cell death have been suggested to be activated upon ZIKV infection, yet the detailed mechanism is not well understood. In the present study, we investigated the effects of ZIKV-encoded proteins in the activation of p53 signaling pathway and found that, among the ten viral proteins,the nonstructural protein 5(NS5) of ZIKV most significantly activated the transcription of p53 target genes. Using the immunoprecipitation-coupled mass spectrometry approach, we identified that ZIKV-NS5 interacted with p53 protein. The NS5-p53 interaction was further confirmed by co-immunoprecipitation and GST pull-down assays. In addition, the MTase domain of NS5 and the C-terminal domain of p53 were mapped to be responsible for the interaction between these two proteins. We further showed that ZIKV-NS5 was colocalized with p53 and increased its protein level in the nuclei and able to prolong the half-life of p53. Furthermore, lentivirus-mediated expression of ZIKV-NS5 in hNPCs led to an apparent cell death phenotype. ZIKV-NS5 promoted the cleavage of PARP1 and significantly increased the cell apoptosis of h NPCs.Taken together, these findings revealed that ZIKV-NS5 is a previously undiscovered regulator of p53-mediated apoptosis in hNPCs, which may contribute to the ZIKV-caused abnormal neurodevelopment.

Generation and Application of a Luciferase Reporter Virus Based on Yellow Fever Virus 17D

Yellow fever virus(YFV) is a re-emerging virus that can cause life-threatening yellow fever disease in humans.Despite the availability of an effective vaccine,little is known about the replication mechanism of YFV,and there are still no available specific anti-YFV medicines.Herein,by introducing the Renilla luciferase gene(Rluc) into an infectious clone of YFV vaccine strain 17 D,we generated a recombinant virus 17 D-Rluc.2 A via reverse genetics approaches.The 17 D-Rluc.2 A had similar plaque morphology and comparable in vitro growth characteristics with its parental strain.Importantly,the reporter luciferase was efficiently expressed in 17 D-Rluc.2 A-infected mammalian and mosquito cells,and there was a good linear correlation between intracellular luciferase expression and extracellular infectious virion reproduction.Furthermore,by a combination of the 17 D-Rluc.2 A reporter virus and selective 2’-hydroxyl acylation analyzed by primer extension(SHAPE)technology,the conserved 5’-SLA element was shown to be essential for YFV replication,highlighting the capability of17 D-R1 uc.2 A in the investigation of YFV replication.At last,we demonstrated that two compounds with distinct anti-viral mechanisms can effectively inhibit the viral propagation in 17 D-Rluc.2 A-infected cells,demonstrating its potential application in the evaluation of anti-viral medicines.Taken together,the 17 D-Rluc.2 A serves as a useful tool for the study of YFV replication and anti-YFV medicine development.

Old Weapon for New Enemy:Drug Repurposing for Treatment of Newly Emerging Viral Diseases

Emerging and re-emerging viral diseases are a public health concern for the whole world and pose a major threat to human health and life.In last decades,numerous major outbreaks of emerging and re-emerging viral diseases with gross public concern were recorded in different regions,including Ebola in western Africa,Zika in South America.

Safety and Considerations of the COVID-19 Vaccine Massive Deployment

Emerging and re-emerging infectious diseases represent a significant and growing cause of morbidity and mortality.Since vaccination campaigns were carried out,several infectious diseases have been controlled successfully,such as smallpox and poliomyelitis,making vaccination one of the most reliable and cost-effective public health interventions.In the long run,vaccine coverage,whether high or low,has been shown to yield important public health benefits(Weycker et al.2005).Therefore,vaccines play an important role in increasing population immunity,preventing severe infectious diseases。

Modulating the tumor microenvironment via oncolytic virus and PI3K inhibition synergistically restores immune checkpoint therapy response in PTEN-deficient glioblastoma

Dear Editor,Glioblastoma(GBM)is a lethal primary brain cancer,with a median survival of less than 2 years.1 Immune checkpoint blockades(ICBs)have revolutionized cancer therapy in the last decade,but they have little clinical benefit in GBM.1 Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations in GBM patients resistant to ICBs.2 PTEN deficiency activates the phosphatidylinositol 3-kinase(PI3K)-AKT pathway to shape an immunosuppressive microenvironment.

A novel phosphorylation site in SARS-CoV-2 nucleocapsid regulates its RNA-binding capacity and phase separation in host cells

Dear Editor,The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a novel emerging coronavirus that has spread worldwide since breaking out in late 2019 and has led to hundreds of millions of infections and millions of human deaths(Zhou et al.,2020).The genome of SARS-CoV-2 encodes 29 viral proteins.

B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

Suppression of UsP8 sensitizes cells to ferroptosis via SQSTM1/p62-mediated ferritinophagy

Dear Editor,Ferroptosis is a newly discovered form of regulated cell death characterized by increased intracellular iron accumulation and subsequent lipid peroxidation(Dixon et al.,2012).Studies have revealed that ferroptosis plays an important role in multiple physiological and pathological processes including degenerative diseases,carcinogenesis,and cancer immunotherapy(Hassannia et al.,2019,Wang et al.,2019).