scholarly journals USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination

Author(s):  
Yingchong Wang ◽  
Qi Li ◽  
Dingwen Hu ◽  
Daolong Gao ◽  
Wenbiao Wang ◽  
...  

Zika virus (ZIKV) is a mosquito-borne flavivirus, and its infection may cause severe neurodegenerative diseases. The outbreak of ZIKV in 2015 in South American has caused severe human congenital and neurologic disorders. Thus, it is vitally important to figure out inner mechanism of ZIKV infection. Here, our data suggested that the ubiquitin-specific peptidase 38 (USP38) played an important role in host resistance to ZIKV infection, during which ZIKV infection did not affect USP38 expression. Mechanistically, USP38 bound to ZIKV envelope (E) protein through its C-terminal domain and attenuated its K48-linked and K63-linked polyubiquitination, thereby repressed the infection of ZIKV. In addition, we found that the deubiquitinase activity of USP38 was essential to inhibit ZIKV infection, and the mutant that lacked the deubiquitinase activity of USP38 lost ability to inhibit the infection. In conclusion, we found a novel host protein USP38 against ZIKV infection, and this may represent a potential therapeutic target for the treatment and prevention of ZIKV infection.

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2029
Author(s):  
Yingchong Wang ◽  
Qin Li ◽  
Dingwen Hu ◽  
Daolong Gao ◽  
Wenbiao Wang ◽  
...  

Zika virus (ZIKV) is a mosquito-borne flavivirus, and its infection may cause severe neurodegenerative diseases. The outbreak of ZIKV in 2015 in South America has caused severe human congenital and neurologic disorders. Thus, it is vitally important to determine the inner mechanism of ZIKV infection. Here, our data suggested that the ubiquitin-specific peptidase 38 (USP38) played an important role in host resistance to ZIKV infection, during which ZIKV infection did not affect USP38 expression. Mechanistically, USP38 bound to the ZIKV envelope (E) protein through its C-terminal domain and attenuated its K48-linked and K63-linked polyubiquitination, thereby repressed the infection of ZIKV. In addition, we found that the deubiquitinase activity of USP38 was essential to inhibit ZIKV infection, and the mutant that lacked the deubiquitinase activity of USP38 lost the ability to inhibit infection. In conclusion, we found a novel host protein USP38 against ZIKV infection, and this may represent a potential therapeutic target for the treatment and prevention of ZIKV infection.


2017 ◽  
Vol 56 (3) ◽  
Author(s):  
Lakshmanane Premkumar ◽  
Matthew Collins ◽  
Stephen Graham ◽  
Guei-Jiun Alice Liou ◽  
Cesar A. Lopez ◽  
...  

ABSTRACT Zika virus (ZIKV) is an emerging flavivirus that can cause birth defects and neurologic complications. Molecular tests are effective for diagnosing acute ZIKV infection, although the majority of infections produce no symptoms at all or present after the narrow window in which molecular diagnostics are dependable. Serology is a reliable method for detecting infections after the viremic period; however, most serological assays have limited specificity due to cross-reactive antibodies elicited by flavivirus infections. Since ZIKV and dengue virus (DENV) widely cocirculate, distinguishing ZIKV infection from DENV infection is particularly important for diagnosing individual cases or for surveillance to coordinate public health responses. Flaviviruses also elicit type-specific antibodies directed to non-cross-reactive epitopes of the infecting virus; such epitopes are attractive targets for the design of antigens for development of serological tests with greater specificity. Guided by comparative epitope modeling of the ZIKV envelope protein, we designed two recombinant antigens displaying unique antigenic regions on domain I (Z-EDI) and domain III (Z-EDIII) of the ZIKV envelope protein. Both the Z-EDI and Z-EDIII antigens consistently detected ZIKV-specific IgG in ZIKV-immune sera but not cross-reactive IgG in DENV-immune sera in late convalescence (>12 weeks postinfection). In contrast, during early convalescence (2 to 12 weeks postinfection), secondary DENV-immune sera and some primary DENV-immune sera cross-reacted with the Z-EDI and Z-EDIII antigens. Analysis of sequential samples from DENV-immune individuals demonstrated that Z-EDIII cross-reactivity peaked in early convalescence and declined steeply over time. The Z-EDIII antigen has much potential as a diagnostic antigen for population-level surveillance and for detecting past infections in patients.


Virulence ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 1795-1807
Author(s):  
Dingwen Hu ◽  
Yingchong Wang ◽  
Aixin Li ◽  
Qin Li ◽  
Caifeng Wu ◽  
...  

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii3-ii3
Author(s):  
Matthew Sherwood ◽  
Robert Ewing ◽  
Carolini Kaid ◽  
Thiago Giove Mitsugi ◽  
Keith Okamoto

Abstract Malignant paediatric nervous system tumours, such as Medulloblastoma, Neuroblastoma and ATRT commonly harbour tumour cells with stem-like features which are highly tumorigenic and resistant to conventional cancer therapies. These tumours can exhibit high lethality and may result in severe sequelae, including cognitive and motor deficits that significantly affect patients’ quality of life. Oncolytic virotherapy is a novel therapy class that exploits viruses that preferentially infect and destroy tumour cells. These viruses present a unique advantage in targeting highly heterogeneous cancers, such as nervous system tumours, as they possess a secondary mechanism of action through which they induce a tumour-specific immune response. Clinical studies employing oncolytic virotherapy have in general reported low toxicity and minimal adverse effects, deeming oncolytic virotherapy as a potentially attractive and safer intervention against paediatric tumours. The Zika virus (ZIKV) is capable of infecting and destroying neural stem-like cancer cells from human embryonal Central Nervous System (CNS) tumours in vitro and in vivo. Infection of CNS tumour cells with ZIKV effectively inhibits tumour metastasis in mice and, in some cases, induces complete tumour remission. Neuroblastoma arises from immature nerve cells and multiple Neuroblastoma cell lines are susceptible to ZIKV infection and oncolysis. These initial findings have demonstrated the potential for a ZIKV-based virotherapy against paediatric nervous system tumours and warrants examination into the molecular mechanisms through which ZIKV executes its oncolytic ability. My research goal is to elucidate the mechanisms which are of paramount importance for ZIKV-induced oncolysis of brain tumour and Neuroblastoma cells. Utilising global expression omics profiling of ZIKV infection and mapping of viral protein-host protein interactions will identify these mechanisms both at the cellular pathway and molecular levels. These collectively will inform our understanding of how we can employ a future ZIKV-based virotherapy against paediatric nervous system tumours.


2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Minu Nain ◽  
Sriparna Mukherjee ◽  
Sonali Porey Karmakar ◽  
Adrienne W. Paton ◽  
James C. Paton ◽  
...  

ABSTRACT Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the leading cause of viral encephalitis in Southeast Asia with potential to become a global pathogen. Here, we identify glucose-regulated protein 78 (GRP78) as an important host protein for virus entry and replication. Using the plasma membrane fractions from mouse neuronal (Neuro2a) cells, mass spectroscopy analysis identified GRP78 as a protein interacting with recombinant JEV envelope protein domain III. GRP78 was found to be expressed on the plasma membranes of Neuro2a cells, mouse primary neurons, and human epithelial Huh-7 cells. Antibodies against GRP78 significantly inhibited JEV entry in all three cell types, suggesting an important role of the protein in virus entry. Depletion of GRP78 by small interfering RNA (siRNA) significantly blocked JEV entry into Neuro2a cells, further supporting its role in virus uptake. Immunofluorescence studies showed extensive colocalization of GRP78 with JEV envelope protein in virus-infected cells. This interaction was also confirmed by immunoprecipitation studies. Additionally, GRP78 was shown to have an important role in JEV replication, as treatment of cells post-virus entry with subtilase cytotoxin that specifically cleaved GRP78 led to a substantial reduction in viral RNA replication and protein synthesis, resulting in significantly reduced extracellular virus titers. Our results indicate that GRP78, an endoplasmic reticulum chaperon of the HSP70 family, is a novel host factor involved at multiple steps of the JEV life cycle and could be a potential therapeutic target. IMPORTANCE Recent years have seen a rapid spread of mosquito-borne diseases caused by flaviviruses. The flavivirus family includes West Nile, dengue, Japanese encephalitis, and Zika viruses, which are major threats to public health with potential to become global pathogens. JEV is the major cause of viral encephalitis in several parts of Southeast Asia, affecting a predominantly pediatric population with a high mortality rate. This study is focused on identification of crucial host factors that could be targeted to cripple virus infection and ultimately lead to development of effective antivirals. We have identified a cellular protein, GRP78, that plays a dual role in virus entry and virus replication, two crucial steps of the virus life cycle, and thus is a novel host factor that could be a potential therapeutic target.


Nature ◽  
2020 ◽  
Vol 585 (7825) ◽  
pp. 414-419 ◽  
Author(s):  
Maria I. Giraldo ◽  
Hongjie Xia ◽  
Leopoldo Aguilera-Aguirre ◽  
Adam Hage ◽  
Sarah van Tol ◽  
...  

2018 ◽  
Author(s):  
Azia S. Evans ◽  
Nicholas J. Lennemann ◽  
Ka man Fan ◽  
Carolyn B. Coyne

AbstractThe flavivirus genus, which includes dengue virus (DENV) and Zika virus (ZIKV), are significant human pathogens and the prevalence of infected vectors continues to geographically expand. Both DENV and ZIKV rely on expansion of the endoplasmic reticulum (ER) and the induction of autophagy to establish a productive viral infection. However, little is known regarding the interplay between the requirements for autophagy initiation during infection and the mechanisms used by these viruses to avoid clearance through the autophagic pathway. We recently showed that DENV and ZIKV inhibit reticulophagy (specific degradation of the ER through autophagy) by cleaving reticulophagy regulator 1 (RETREG1), an autophagy receptor responsible for targeted ER sheet degradation. These data suggest that DENV and ZIKV require specific autophagic pathways for their replication, while other autophagic pathways are antiviral. We previously identified BPI Fold Containing Family B Member 3 (BPIFB3) as a regulator of autophagy that negatively controls enterovirus replication. Here, we show that in contrast to enteroviruses, BPIFB3 functions as a positive regulator of DENV and ZIKV infection and that its RNAi-mediated silencing drastically inhibits the formation of viral replication organelles. We show that BPIFB3 depletion enhances ER fragmentation, while its overexpression protects against autophagy-induced ER degradation, demonstrating that BPIFB3 serves as a specific regulator of ER turnover. We further show that the antiviral effects of BPIFB3 depletion on flavivirus infection are reversed in RETREG1-depleted cells, and that BPIFB3 associates with RETREG1 within the ER, suggesting that BPIFB3 regulates a RETREG1-specific reticulophagy pathway. Collectively, these studies identify BPIFB3 as a regulator of the reticulophagy pathway and define the requirements for a novel host regulator of flavivirus infection.Author SummaryFlaviviruses and other arthropod transmitted viruses represent a widespread global health problem with limited treatment options currently available. Thus, greater knowledge of the host factors required for replication and transmission is needed to provide a better understanding of the cellular requirements for infection. Here, we show that the endoplasmic reticulum (ER) localized protein, BPIFB3 is required to facilitate flavivirus infection. Depletion of BPIFB3 in cells inhibits dengue virus and Zika virus infection prior to replication of the viral genome. Mechanistically, we show that BPIFB3 inhibits ER degradation in an autophagy-specific manner and that loss of BPIFB3 decreases the availability of ER membranes needed for flavivirus replication. We further show that BPIFB3 specifically regulates the RETREG1 pathway, but not other pathways of ER turnover. Together, our data define a previously uncharacterized method of regulating ER degradation and show that BPIFB3 is an essential host factor for a productive flavivirus infection.


2016 ◽  
Vol 37 (4) ◽  
pp. 170 ◽  
Author(s):  
William Rawlinson

Zika virus (ZIKV) infections have been recognised in Africa and Asia since 1940. The virus is in the family Flaviviridae and genus Flavivirus, along with Dengue, Japanese encephalitis virus, Tick borne encephalitis, West Nile virus, and Yellow fever virus. These viruses share biological characteristics of an envelope, icosahedral nucleocapsid, and a non-segmented, positive sense, single-strand RNA genome of ~10kb encoding three structural proteins (capsid C pre-membrane/membrane PrM/M, envelope E), and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). ZIKV has three known genotypes; the West African (Nigerian cluster), East African (MR766 prototype cluster), and Asian strains. Virus sequencing from the most recent South American outbreak suggests this virus is related to the 2013 French Polynesian isolates of Asian lineage.


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