Ming-Liang He

Virus infection stimulates proto‐oncoprotein PIM1 kinase expression, but its importance and the biological functions of this process are poorly understood. Herein, PIM1 promotes IFNAR1 degradation to attenuate cellular innate immunity during human coronavirus HCoV‐OC43 infection. During virus replication, the double‐stranded viral RNA and some viral proteins upregulate PIM1 expression, which phosphorylates E3 ubiquitin ligase β‐TrCP1 at Serine 82. The pS82‐β‐TrCP1 then forms a complex with S535/S539‐phosphorylated interferon receptor IFNAR1 (pS535/539‐IFNAR1), leading to IFNAR1 ubiquitination and degradation. Both pan‐inhibitors (CX‐6528, SGI‐1776, AZD‐1208) and a specific inhibitor of PIM1 kinase (PIM1 inhibitor 2) effectively block this process and potently inhibit viral replication. This studies demonstrate a novel strategy that viruses use to disrupt cellular innate immunity, suggesting a potential therapeutic target for further anti‐virus drug development.

Incurable infection by herpes simplex virus 1 (HSV‐1) can cause severe encephalitis and neurodegenerative diseases, e.g., Alzheimer's disease (AD) and amyotrophic lateral sclerosis. How HSV‐1 reaches the brain from the initial infection site remains inconclusive. Here, an innovative approach combining carbon quantum dots (CQDs) with dissolving microneedles (dMN) for real‐time tracking of HSV‐1 from skin to brain is presented. Upon application, CQDs‐HSV‐1 is released from the dMN through the swelling of interstitial fluid (ISF) in skin and subsequently monitored by living imaging. Remarkably, it is observed that HSV‐1 preferentially infects peripheral skin nerves, almost all viruses directly enter to brain via the spinal cord within 10–30 min, while few viruses enter the brain through the bloodstream via tail vein injection at the same time. Spinal cord injury (SCI) significantly delays the HSV‐1 transport from skin to brain but has no effect on the virus's travel from blood to brain. In a microfluid system, HSV‐1 shows preferential neurite infection, then transports to the cell body of differentiated SH‐SY5Y cells, highlighting the viral traffic process in neurons. The integration of CQDs‐virus labelling technology and dMN delivery model presents a promising tool for investigating the in vivo transport routes of neurotropic viruses with initial skin infections.

Hepatocellular carcinoma (HCC) is characterized by poor prognosis and remains a leading cause of cancer mortality worldwide. Advanced HCC is managed with several first-line therapies, including tyrosine kinase inhibitors (TKI) and immunotherapy (mAb-PD-1 and mAb-VEGF). However, the efficacy of HCC therapeutics is often short-lived. Recent studies have demonstrated that the activation of the Nrf2-Bcl-xL pathway contributes to poor prognosis in a subset of HCC patients. Here, we found that dimethyl fumarate (DMF), a drug used for treating psoriasis and multiple sclerosis, regulates the Nrf2-Bcl-xL signaling axis to inhibit HCC growth in a mice xenograft model. Mechanistically, the downregulation of the Nrf2-Bcl-xL axis led to mitochondria stress and apoptosis in vitro and in vivo. Enforced Nrf2 or Bcl-xL expression in HCC cells markedly reversed the antitumor effects of DMF in HCC cells. Importantly, DMF enhanced sorafenib’s antitumor effects. Collectively, our results demonstrate new mechanism insights into the antitumor effects of DMF and that Nrf2-targeted therapy might improve HCC treatment outcomes.

Enterovirus A71 (EV‐A71) is a positive‐sense single‐stranded RNA virus, which hijacks host proteins to benefit viral internal ribosome entry site (IRES)‐dependent protein translation and further propagation. We demonstrated that serine 78 (S78) phosphorylation of Hsp27 is critical for Hsp27/hnRNP A1 relocalization upon EV‐A71 infection. Here, we report that the deletion of WDPF and ACD domains disturbs subcellular localization of Hsp27, resulting in partial nuclear translocation. The domain deletion‐induced Hsp27 nuclear translocation fails to direct hnRNP A1 translocation. The 2A^pro‐induced IRES activity and viral replication are suppressed by the deletion of WDPF or ACD domain. Surprisingly, a peptide (WDPF) dramatically inhibits S78 phosphorylation. Therefore, hnRNP A1 translocation, viral IRES activity, and viral protein translation and propagation are all strongly suppressed by the WDPF peptide, but not by peptide without WDPFR sequence (ΔWDPF). Moreover, the WDPF peptide also has potent antiviral activity on other RNA virus (e.g., coronavirus HCoV‐OC43) and DNA virus (e.g., HSV‐1 and HBV). Peptide treatment with kinase inhibitor Sorafenib brings an additional inhibitory effect on HCoV‐OC43 and HSV‐1. Taken together, we uncover a crucial role of WDPF domain in S78 phosphorylation for EV‐A71‐induced hnRNP A1 nuclear translocation, IRES‐dependent viral protein translation, and EV‐A71 propagation. Our results explore a new path for target‐based pan‐antiviral strategy.

It is believed that DNA double-strand breaks induced by Zika virus (ZIKV) infection in pregnant women is a main reason of brain damage (e.g. microcephaly, severe brain malformation, and neuropathy) in newborn babies [1,2], but its underlying mechanism is poorly understood. In this study, we report that the depletion of ERp57, a member of the protein disulphide isomerase (PDI) family, leads to the limited production of ZIKV in nerve cells. ERp57 knockout not only suppresses viral induced reactive oxygen species (ROS) mediated host DNA damage, but also decreases apoptosis. Strikingly, DNA damage depends on ERp57-bridged complex formation of viral protein NS2B/NS3. LOC14, an ERp57 inhibitor, restricts ZIKV infection and virus-induced DNA damage. Our work reveals an important role of ERp57 in both ZIKV propagation and virus-induced DNA damage, suggesting a potential target against ZIKV infection.

A positive-sense (+) single-stranded RNA (ssRNA) virus (e.g. enterovirus A71, EV-A71) depends on viral polypeptide translation for initiation of virus replication after entry. We reported that EV-A71 hijacks Hsp27 to induce hnRNP A1 cytosol redistribution to initiate viral protein translation, but the underlying mechanism is still elusive. Here, we show that phosphorylation-deficient Hsp27-3A (Hsp27^S15/78/82A) and Hsp27^S78A fail to translocate into the nucleus and induce hnRNP A1 cytosol redistribution, while Hsp27^S15A and Hsp27^S82A display similar effects to the wild type Hsp27. Furthermore, we demonstrate that the viral 2A protease (2A^pro) activity is a key factor in regulating Hsp27/hnRNP A1 relocalization. Hsp27^S78A dramatically decreases the IRES activity and viral replication, which are partially reduced by Hsp27^S82A. However, Hsp27^S15A displays the same activity as the wild-type Hsp27. Peptide S78 potently suppresses EV-A71 protein translation and reproduction through blockage of EV-A71-induced Hsp27 phosphorylation and Hsp27/hnRNP A1 relocalization. A point mutation (S78A) on S78 impairs its inhibitory functions on Hsp27/hnRNP A1 relocalization and viral replication. Taken together, we demonstrate the importance of Ser78 phosphorylation of Hsp27 regulated by virus infection in nuclear translocation, hnRNP A1 cytosol relocation, and viral replication, suggesting a new path (such as peptide S78) for target-based antiviral strategy.

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although has faded from public view, the virus itself remains highly active and continues to mutate, continuously causing infections.

The crucial role of interferon (IFN) signaling is well known in the restriction or eradication of pathogen invasion. Viruses take a variety of ways to antagonize host defense through eliminating IFN-signaling intracellularly for decades. However, the way by viruses target IFN-signaling extracellularly has not been discovered. Infection by both coronavirus SARS-CoV-2 and enterovirus 71 (EV71 or EV-A71) can cause severe diseases such as neurological disorders and even death in children.^1–3 Here, we show evidence that the protease of SARS-CoV-2 (3CL^pro) and EV71 (2A^pro) upregulates the expression and secretion of LDL-receptor-related protein-associated protein 1 (LRPAP1). As a ligand, the N-terminus of secreted LRPAP1 binds with the extracellular domain of IFNAR1 that triggers the receptor ubiquitination and degradation and promotes virus infection both in vitro, ex vivo in the mouse brain, and in vivo in newborn mice. A small peptide from the N-terminus of LRPAP1 effectively binds and causes IFNAR1 degradation that enhances both DNA and RNA viral infections, including herpesvirus HSV-1, hepatitis B virus (HBV), EV71, and beta-coronavirus HCoV-OC43; whereas α2M, a LRPAP1 inhibitor, arrests virus infections by stabilizing IFNAR1. Our study demonstrates a new mechanism used by viruses for evading host cell immunity, supporting a strategy for developing pan-antiviral drugs.

Conventional light-driven cancer therapeutics require oxygen and visible light to indirectly damage biomolecules, limiting their efficacy in deep, hypoxic tumours. Here we report the use of near-infrared-activated small-molecule Pt(IV) photooxidants to directly oxidize intracellular biomolecules in an oxygen-independent manner, achieving controllable and effective elimination of cancer stem cells. These Pt(IV) complexes accumulate in the endoplasmic reticulum and show low toxicity in the dark. Upon irradiation, the resultant metal-enhanced photooxidation effect causes them to robustly photooxidize survival-related biomolecules, induce intense oxidative stress, disrupt intracellular pH (pHi) homeostasis and initiate nonclassical necrosis. In vivo experiments confirm that the lead photooxidant can effectively inhibit tumour growth, suppress metastasis and activate the immune system. Our study validates the concept of metal-enhanced photooxidation and the subsequent chemotherapeutic applications, supporting the development of such localized photooxidants to directly damage intracellular biomolecules and decrease pHi as a strategy for effective metal-based drugs.

The coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden to our society. Most patients infected by SARS-CoV-2 are asymptomatic or have mild symptoms. Although only a small proportion of patients progressed to severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, and cardiovascular disorders, severe COVID-19 is accompanied by high mortality rates with near 7 million deaths. Nowadays, effective therapeutic patterns for severe COVID-19 are still lacking. It has been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate host metabolism to avoid immunity, facilitate their own replication, or to initiate pathological response. Targeting the interaction between SARS-CoV-2 and host metabolism holds promise for developing therapeutic strategies. In this review, we summarize and discuss recent studies dedicated to uncovering the role of host metabolism during the life cycle of SARS-CoV-2 in aspects of entry, replication, assembly, and pathogenesis with an emphasis on glucose metabolism and lipid metabolism. Microbiota and long COVID-19 are also discussed. Ultimately, we recapitulate metabolism-modulating drugs repurposed for COVID-19 including statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, and metformin.