A LY6E-PHB1-TRIM21 assembly degrades CD14 protein to mitigate LPS-induced inflammatory response.

A major theme of host against invading pathogens lies in multiple regulatory nodes that ensure sufficient signals for protection while avoiding excessive signals toward over-inflammation. The TLR4/MD-2/CD14 complex receptor-mediated response to bacterial lipopolysaccharide (LPS) represents a paradigm for understanding the proper control of anti-pathogen innate immunity. In this study, we studied the mechanism by which the glycosylphosphatidylinositol (GPI)-linked LY6E protein constrains LPS response via downregulating CD14. We first showed that LY6E downregulated CD14 via ubiquitin-dependent proteasomal degradation. The subsequent profiling of LY6E protein interactome led to the revelation that the degradation of CD14 by LY6E requires PHB1, which interacts with CD14 in a LY6E-dependent manner. Finally, we identified the PHB1-interacting TRIM21 as the major ubiquitin E3 ligase for the LY6E-mediated ubiquitination of CD14. Together, our study elucidated the molecular basis of LY6E-mediated governance of LPS response, alongside providing new insights to regulatory mechanisms controlling the homeostasis of membrane proteins.

Nonmuscle myosin IIA promotes the internalization of influenza A virus and regulates viral polymerase activity through interacting with nucleoprotein in human pulmonary cells.

Influenza A virus (IAV), responsible for seasonal epidemics and recurring pandemics, represents a global threat to public health. Given the risk of a potential IAV pandemic, it is increasingly important to better understand virus-host interactions and develop new anti-viral strategies. Here, we reported nonmuscle myosin IIA (MYH9)-mediated regulation of IAV infection. MYH9 depletion caused a profound inhibition of IAV infection by reducing viral attachment and internalization in human lung epithelial cells. Surprisingly, overexpression of MYH9 also led to a significant reduction in viral productive infection. Interestingly, overexpression of MYH9 retained viral attachment, internalization, or uncoating, but suppressed the viral ribonucleoprotein (vRNP) activity in a minigenome system. Further analyses found that excess MYH9 might interrupt the formation of vRNP by interacting with the viral nucleoprotein (NP) and result in the reduction of the completed vRNP in the nucleus, thereby inhibiting subsequent viral RNA transcription and replication. Together, we discovered that MYH9 can interact with IAV NP protein and engage in the regulation of vRNP complexes, thereby involving viral replication. These findings enlighten new mechanistic insights into the complicated interface of host-IAV interactions, ultimately making it an attractive target for the generation of antiviral drugs.

Angiotensin-Converting Enzyme 2 Potentiates SARS-CoV-2 Infection by Antagonizing Type I Interferon Induction and Its Down-Stream Signaling Pathway.

The innate interferon (IFN) response constitutes the first line of host defense against viral infections. It has been shown that IFN-I/III treatment could effectively contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro. However, how SARS-CoV-2 survives through the innate antiviral mechanism remains to be explored. Our study uncovered that human angiotensin-converting enzyme 2 (ACE2), identified as a primary receptor for SARS-CoV-2 entry, can disturb the IFN-I signaling pathway during SARS-CoV-2 infection in human lung cells. We identified that ACE2 was significantly upregulated by SARS-CoV-2 and Sendai virus (SeV) infection, and exogenous expression of ACE2 suppressed IFN-I production in a dose-dependent manner. Mechanistically, ACE2 disrupted poly (I:C)-mediated inhibition of SARS-CoV2 replication by antagonizing IFN-I production by blocking IRF3 phosphorylation and nuclear translocation. Moreover, ACE2 quenched the IFN-mediated antiviral immune response by degrading endogenous STAT2 protein, inhibiting STAT2 phosphorylation and nuclear translocation. Interestingly, IFN-inducible short ACE2 (dACE2 or MIRb-ACE2) can also be induced by virus infection and inhibits the IFN signaling. Thus, our findings provide mechanistic insight into the distinctive role of ACE2 in promoting SARS-CoV-2 infection and enlighten us that the development of interventional strategies might be further optimized to interrupt ACE2-mediated suppression of IFN-I and its signaling pathway. IMPORTANCE Efficient antiviral immune responses against SARS-CoV-2 infection play a key role in controlling the coronavirus diseases 2019 (COVID-19) caused by this virus. Although SARS-CoV-2 has developed strategies to counteract the IFN-I signaling through the virus-derived proteins, our knowledge of how SARS-CoV-2 survives through the innate antiviral mechanism remains poor. We herein discovered the distinctive role of ACE2 as a restraining factor of the IFN-I signaling in facilitating SARS-CoV-2 infection in human lung cells. Both full-length ACE2 and truncated dACE2 can antagonize IFN-mediated antiviral response. These findings are key to understanding the counteraction between SARS-CoV-2 pathogenicity and the host antiviral defenses.

Placental Alkaline Phosphatase Promotes Zika Virus Replication by Stabilizing Viral Proteins through BIP.

Zika virus (ZIKV) infection during pregnancy causes intrauterine growth defects and microcephaly, but knowledge of the mechanism through which ZIKV infects and replicates in the placenta remains elusive. Here, we found that ALPP, an alkaline phosphatase expressed primarily in placental tissue, promoted ZIKV infection in both human placental trophoblasts and astrocytoma cells. ALPP bound to ZIKV structural and nonstructural proteins and thereby prevented their proteasome-mediated degradation and enhanced viral RNA replication and virion biogenesis. In addition, the function of ALPP in ZIKV infection depends on its phosphatase activity. Furthermore, we demonstrated that ALPP was stabilized through interactions with BIP, which is the endoplasmic reticulum (ER)-resident heat shock protein 70 chaperone. The chaperone activity of BIP promoted ZIKV infection and mediated the interaction between ALPP and ZIKV proteins. Collectively, our findings reveal a previously unrecognized mechanism through which ALPP facilitates ZIKV replication by coordinating with the BIP protein.IMPORTANCE ZIKV is a recently emerged mosquito-borne flavivirus that can cause devastating congenital Zika syndrome in pregnant women and Guillain-Barré syndrome in adults, but how ZIKV specifically targets the placenta is not well understood. Here, we identified an alkaline phosphatase (ALPP) that is expressed primarily in placental tissue and promotes ZIKV infection by colocalizing with ZIKV proteins and preventing their proteasome-mediated degradation. The phosphatase activity of ALPP could be required for optimal ZIKV infection, and ALPP is stabilized by BIP via its chaperone activity. This report provides novel insights into host factors required for ZIKV infection, which potentially has implications for ZIKV infection of the placenta.

Internal Gene Cassette From a Human-Origin H7N9 Influenza Virus Promotes the Pathogenicity of H9N2 Avian Influenza Virus in Mice.

H9N2 avian influenza virus is one of the most widely circulating viruses in poultry and poses a huge potential threat to human health due to its frequent gene reassortment with other influenza viruses. In this study, we generated a series of H9N2-H7N9 reassortant viruses and examined their pathogenicity in a mouse model. We found that HA or combined HA and NA replacement on the H9N2 background led to no substantial change in the virus-induced pathogenicity, whereas H9N2 virus containing H7N9 internal genes had significantly higher virulence in comparison to the parental H9N2 virus. This increased pathogenicity is associated with enhanced viral replication both in mice and in MDCK cells. We further demonstrated that the viral ribonucleoprotein complex from H7N9 virus possessed higher activity than that from its H9N2 counterpart. Collectively, our data demonstrated that genetic compatibility between H9N2 and H7N9 viruses facilitated the reassortment between H7N9 and H9N2 viruses co-circulated in poultry and that internal gene replacement would convert H9N2 virus into a novel threat to human health.