Dataset Information

USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination.

ABSTRACT: 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8538320 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination.

Wang Yingchong Y Li Qin Q Hu Dingwen D Gao Daolong D Wang Wenbiao W Wu Kailang K Wu Jianguo J

Viruses 20211008 10

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. ...[more]

PMID: 34696459

Similar Datasets

Project description:Zika virus (ZIKV) is an emerging mosquito-borne flavivirus. Recent ZIKV outbreaks have produced serious human disease, including neurodevelopmental malformations (congenital Zika syndrome) and Guillain-Barré syndrome. These outcomes were not associated with ZIKV infection prior to 2013, raising the possibility that viral genetic changes could contribute to new clinical manifestations. All contemporary ZIKV isolates encode an N-linked glycosylation site in the envelope (E) protein (N154), but this glycosylation site is absent in many historical ZIKV isolates. Here, we investigated the role of E protein glycosylation in ZIKV pathogenesis using two contemporary Asian-lineage strains (H/PF/2013 and PRVABC59) and the historical African-lineage strain (MR766). We found that glycosylated viruses were highly pathogenic in Ifnar1-/- mice. In contrast, nonglycosylated viruses were attenuated, producing lower viral loads in the serum and brain when inoculated subcutaneously but remaining neurovirulent when inoculated intracranially. These results suggest that E glycosylation is advantageous in the periphery but not within the brain. Accordingly, we found that glycosylation facilitated infection of cells expressing the lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) or DC-SIGN-related (DC-SIGNR), suggesting that inefficient infection of lectin-expressing leukocytes could contribute to the attenuation of nonglycosylated ZIKV in mice.IMPORTANCE It is unclear why the ability of Zika virus (ZIKV) to cause serious disease, including Guillain-Barré syndrome and birth defects, was not recognized until recent outbreaks. One contributing factor could be genetic differences between contemporary ZIKV strains and historical ZIKV strains. All isolates from recent outbreaks encode a viral envelope protein that is glycosylated, whereas many historical ZIKV strains lack this glycosylation. We generated nonglycosylated ZIKV mutants from contemporary and historical strains and evaluated their virulence in mice. We found that nonglycosylated viruses were attenuated and produced lower viral loads in serum and brains. Our studies suggest that envelope protein glycosylation contributes to ZIKV pathogenesis, possibly by facilitating attachment to and infection of lectin-expressing leukocytes.

Project description:In February 2016, the World Health Organization declared a Public Health Emergency of International Concern on Zika Virus (ZIKV), because of its association with severe fetal anomalies of congenitally infected humans. This has led to urgent efforts by academic, federal, and industry research groups to improve our understanding of the pathogenesis of ZIKV and to develop detection methods, therapeutic strategies, and vaccines. Although we still do not have the entire picture of the pathogenesis of ZIKV, extensive research has been conducted on related pathogenic flaviviruses (i.e., dengue virus, West Nile virus, and yellow fever virus). Binding to glycosaminoglycans (GAGs) through its envelope protein is the first step in successful host cell invasion of dengue virus. In this study, we examined ZIKV envelope protein (ZIKV E) binding to GAGs in a real time interaction study using surface plasmon resonance (SPR) to explore the role of GAGs in host cell entry of ZIKV into placenta and brain. ZIKV E strongly binds (KD = 443 nM) pharmaceutical heparin (HP), a highly sulfated GAG, and binds with lower avidity to less sulfated GAGs, suggesting that the ZIKV E-GAG interaction may be electrostatically driven. Using SPR competition assays with various chain length HP oligosaccharides (from 4 to 18 saccharide units in length), we observed that ZIKV E preferentially binds to longer HP oligosaccharides (with 8-18 saccharides). Next, we examined GAGs prepared from human placentas to determine if they bound ZIKV E, possibly mediating placental cell invasion of ZIKV. Compositional analysis of these GAGs as well as SPR binding studies showed that both chondroitin sulfate and heparan sulfate GAGs, present on the placenta, showed low-micromolar interactions with ZIKV E. Both porcine brain CS and HS also showed micromolar binding with ZIKV E. Moreover, heparan sulfate with a higher TriS content, the dominant repeating unit of HP, shows a high affinity for ZIKV E. These results suggest that GAGs may be utilized as attachment factors for host cell entry of Zika virus as they do in other pathogenic flaviviruses. They may also assist us in advancing our understanding of the pathogenesis of ZIKV and guide us in designing therapeutics to combat ZIKV with more insight.

Dataset Information

USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination.

Publications

USP38 Inhibits Zika Virus Infection by Removing Envelope Protein Ubiquitination.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets