Assembly and activation of EBV latent membrane protein 1.

Latent membrane protein 1 (LMP1) is the primary oncoprotein of Epstein-Barr virus (EBV) and plays versatile roles in the EBV life cycle and pathogenesis. Despite decades of extensive research, the molecular basis for LMP1 folding, assembly, and activation remains unclear. Here, we report cryo-electron microscopy structures of LMP1 in two unexpected assemblies: a symmetric homodimer and a higher-order filamentous oligomer.

RNF213 modulates γ-herpesvirus infection and reactivation via targeting the viral Replication and Transcription Activator.

Interferons (IFNs) and the products of interferon-stimulated genes (ISGs) play crucial roles in host defense against virus infections. Although many ISGs have been characterized with respect to their antiviral activity, their target specificities and mechanisms of action remain largely unknown. Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that is linked to several human malignancies.

TMEΜ45B Interacts with Sindbis Virus Nsp1 and Nsp4 and Inhibits Viral Replication.

Alphavirus infection induces the expression of type I interferons, which inhibit the viral replication by upregulating the expression of interferon-stimulated genes (ISGs). Identification and mechanistic studies of the antiviral ISGs help to better understand how the host controls viral infection and help to better understand the viral replication process. Here, we report that the ISG product TMEM45B inhibits the replication of Sindbis virus (SINV).

HIV-1 exploits the Fanconi anemia pathway for viral DNA integration.

The integration of HIV-1 DNA into the host genome results in single-strand gaps and 2-nt overhangs at the ends of viral DNA, which must be repaired by cellular enzymes. The cellular factors responsible for the DNA damage repair in HIV-1 DNA integration have not yet been well defined. We report here that HIV-1 infection potently activates the Fanconi anemia (FA) DNA repair pathway, and the FA effector proteins FANCI-D2 bind to the C-terminal domain of HIV-1 integrase.

TMEM106A inhibits enveloped virus release from cell surface.

Enveloped viruses pose constant threat to hosts from ocean to land. Virion particle release from cell surface is a critical step in the viral life cycle for most enveloped viruses, making it a common antiviral target for the host defense system. Here we report that host factor TMEM106A inhibits the release of enveloped viruses from the cell surface.

Subunit Nanovaccine with Potent Cellular and Mucosal Immunity for COVID-19.

To combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, we formulated the S1 subunit of the virus with two adjuvants, amphiphilic adjuvant monophosphoryl lipid A for Toll-like receptor 4 and CpG oligodeoxynucleotide for Toll-like receptor 9, into cationic liposomes to produce a potent, safer, and translatable nanovaccine. The nanovaccine can efficiently elicit a humoral immune response and strong IgA antibodies in mice. The sera from the vaccinated mice significantly inhibit SARS-CoV-2 from infecting Vero cells.

Insights into catalysis and regulation of non-canonical ubiquitination and deubiquitination by bacterial deamidase effectors.

The bacterial effector MavC catalyzes non-canonical ubiquitination of host E2 enzyme UBE2N without engaging any of the conventional ubiquitination machinery, thereby abolishing UBE2N's function in forming K63-linked ubiquitin (Ub) chains and dampening NF-кB signaling. We now report the structures of MavC in complex with conjugated UBE2N~Ub and an inhibitor protein Lpg2149, as well as the structure of its ortholog, MvcA, bound to Lpg2149. Recognition of UBE2N and Ub depends on several unique features of MavC, which explains the inability of MvcA to catalyze ubiquitination.

Molecular Mechanism of RNA Recognition by Zinc-Finger Antiviral Protein.

Zinc-finger antiviral protein (ZAP) is a host antiviral factor that specifically restricts a wide range of viruses. ZAP selectively binds to CG-dinucleotide-enriched RNA sequences and recruits multiple RNA degradation machines to degrade target viral RNA. However, the molecular mechanism and structural basis for ZAP recognition of specific RNA are not clear.

Diverse Mechanisms of CRISPR-Cas9 Inhibition by Type IIC Anti-CRISPR Proteins.

Anti-CRISPR proteins (Acrs) targeting CRISPR-Cas9 systems represent natural "off switches" for Cas9-based applications. Recently, AcrIIC1, AcrIIC2, and AcrIIC3 proteins were found to inhibit Neisseria meningitidis Cas9 (NmeCas9) activity in bacterial and human cells. Here we report biochemical and structural data that suggest molecular mechanisms of AcrIIC2- and AcrIIC3-mediated Cas9 inhibition.

Regulation of HIV-1 Gag-Pol Expression by Shiftless, an Inhibitor of Programmed -1 Ribosomal Frameshifting.

Programmed -1 ribosomal frameshifting (-1PRF) is a widely used translation recoding mechanism. HIV-1 expresses Gag-Pol protein from the Gag-coding mRNA through -1PRF, and the ratio of Gag to Gag-Pol is strictly maintained for efficient viral replication. Here, we report that the interferon-stimulated gene product C19orf66 (herein named Shiftless) is a host factor that inhibits the -1PRF of HIV-1.

SUN1 Regulates HIV-1 Nuclear Import in a Manner Dependent on the Interaction between the Viral Capsid and Cellular Cyclophilin A.

Human immunodeficiency virus type 1 (HIV-1) can infect nondividing cells via passing through the nuclear pore complex. The nuclear membrane-imbedded protein SUN2 was recently reported to be involved in the nuclear import of HIV-1. Whether SUN1, which shares many functional similarities with SUN2, is involved in this process remained to be explored.

Identification of new type I interferon-stimulated genes and investigation of their involvement in IFN-β activation.

Virus infection induces the production of type I interferons (IFNs). IFNs bind to their heterodimeric receptors to initiate downstream cascade of signaling, leading to the up-regulation of interferon-stimulated genes (ISGs). ISGs play very important roles in innate immunity through a variety of mechanisms.

The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity.

Cyclic diadenylate monophosphate (c-di-AMP) is secreted by bacteria as a secondary messenger. How immune cells detect c-di-AMP and initiate anti-bacterial immunity remains unknown. We found that the endoplasmic reticulum (ER) membrane adaptor ERAdP acts as a direct sensor for c-di-AMP.

HIV-1 can infect northern pig-tailed macaques (Macaca leonina) and form viral reservoirs in vivo.

Viral reservoirs of HIV-1 are a major obstacle for curing AIDS. The novel animal models that can be directly infected with HIV-1 will contribute to develop effective strategies for eradicating infections. Here, we inoculated 4 northern pig-tailed macaques (NPM) with the HIV-1 strain HIV-1 and monitored the infection for approximately 3years (150weeks).

MicroRNAs recruit eIF4E2 to repress translation of target mRNAs.

MicroRNAs (miRNAs) recruit the RNA-induced silencing complex (RISC) to repress the translation of target mRNAs. While the 5' 7-methylguanosine cap of target mRNAs has been well known to be important for miRNA repression, the underlying mechanism is not clear. Here we show that TNRC6A interacts with eIF4E2, a homologue of eIF4E that can bind to the cap but cannot interact with eIF4G to initiate translation, to inhibit the translation of target mRNAs.

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein.

Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mRNAs and repressing the translation and/or promoting the degradation of target mRNA. In addition, ZAP regulates the expression of certain cellular genes. Here, we report that tripartite motif-containing protein 25 (TRIM25), a ubiquitin E3 ligase, is required for the antiviral activity of ZAP.

LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells.

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC). However, the biology of hepatic CSCs remains largely undefined. Through analysis of transcriptome microarray data, we identify a long noncoding RNA (lncRNA) called lncBRM, which is highly expressed in liver CSCs and HCC tumours.

The Short Form of the Zinc Finger Antiviral Protein Inhibits Influenza A Virus Protein Expression and Is Antagonized by the Virus-Encoded NS1.

Unlabelled: Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses. There are two ZAP isoforms arising from alternative splicing, which differ only at the C termini. It was recently reported that the long isoform (ZAPL) promotes proteasomal degradation of influenza A virus (IAV) proteins PA and PB2 through the C-terminal poly(ADP-ribose) polymerase (PARP) domain, which is missing in the short form (ZAPS), and that this antiviral activity is antagonized by the viral protein PB1.

DNA sensor cGAS-mediated immune recognition.

The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway.

Sindbis Virus Can Exploit a Host Antiviral Protein To Evade Immune Surveillance.

Unlabelled: Viral infection induces production of type I interferons (IFNs), which stimulate the expression of a variety of antiviral factors to inhibit viral replication. To establish effective infection, viruses need to develop strategies to evade the immune responses. A neurovirulent Sindbis virus strain with neuroinvasive properties (SVNI) causes lethal encephalitis in mice, and its replication in cultured cells is inhibited by the zinc finger antiviral protein (ZAP), a host factor that specifically inhibits the replication of certain viruses by binding to the viral mRNAs, repressing the translation of target mRNA, and promoting the degradation of target mRNA.

M2BP inhibits HIV-1 virion production in a vimentin filaments-dependent manner.

M2BP (also called 90K) is an interferon-stimulated gene product that is upregulated in HIV-1 infection. A recent study revealed that M2BP reduces the infectivity of HIV-1 by inhibiting the processing of the viral envelope protein. Here we report that in addition to reducing viral infectivity, M2BP inhibits HIV-1 virion production.

Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs.

Tristetraprolin (TTP) regulates the expression of AU-rich element-containing mRNAs through promoting the degradation and repressing the translation of target mRNA. While the mechanism for promoting target mRNA degradation has been extensively studied, the mechanism underlying translational repression is not well established. Here, we show that TTP recruits eukaryotic initiation factor 4E2 (eIF4E2) to repress target mRNA translation.

HIV-1 Exploits the Host Factor RuvB-like 2 to Balance Viral Protein Expression.

The correct ratio of the HIV-1 structural protein Gag to the envelope protein (Env) is important for maximal virion infectivity. How the virus ensures the production of Gag and Env proteins in an appropriate ratio remains unknown. We report that HIV-1 exploits the host factor RuvB-like 2 (RVB2) to balance relative expression of Gag and Env for efficient production of infectious virions.

YB-1 stabilizes HIV-1 genomic RNA and enhances viral production.

HIV-1 utilizes cellular factors for efficient replication. The viral RNA is different from cellular mRNAs in many aspects, and is prone to attacks by cellular RNA quality control systems. To establish effective infection, the virus has evolved multiple mechanisms to protect its RNA.

ZAP inhibits murine gammaherpesvirus 68 ORF64 expression and is antagonized by RTA.

Zinc finger antiviral protein (ZAP) is an interferon-inducible host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1 and Ebola virus. ZAP functions as a dimer formed through intermolecular interactions of its N-terminal tails. ZAP binds directly to specific viral mRNAs and inhibits their expression by repressing translation and/or promoting degradation of the target mRNA.