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Rabbit Hemorrhagic Disease Virus Non-structural Protein 6 Induces Apoptosis in Rabbit Kidney Cells.

ABSTRACT: Rabbit hemorrhagic disease (RHD) is a highly contagious disease caused by rabbit hemorrhagic disease virus (RHDV). Previous research has shown that RHDV induces apoptosis in numerous cell types, although the molecular mechanisms underlying the apoptosis induced by RHDV are not well understood. One possible factor is non-structural protein 6 (NSP6), a 3C-like protease that plays an important role in processing viral polyprotein precursors into mature non-structural proteins. To fully establish a role for NSP6, the present study examined the effects of ectopic expression of the protein in rabbit (RK13) and human (HeLa and HepG2) cells. We found that NSP6 suppressed cell viability and promoted apoptosis in all three cell types in a dose-dependent manner. We also identified increased caspase-3, -8, and -9 activities in RK13 cell, and an increased Bax to Bcl2 mRNA ratio. Mechanistically, the ability of NSP6 to induce apoptosis was impaired by mutation of the catalytic His27 residue. Our study has shown that RHDV NSP6 can induce apoptosis in host cells and is likely an important contributor to RHDV-induced apoptosis and pathogenesis.

SUBMITTER: Chen M

PROVIDER: S-EPMC6333657 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Rabbit Hemorrhagic Disease Virus Non-structural Protein 6 Induces Apoptosis in Rabbit Kidney Cells.

Chen Mengmeng M Liu Xing X Hu Bo B Fan Zhiyu Z Song Yanhua Y Wei Houjun H Qiu Rulong R Xu Weizhong W Zhu Weifeng W Wang Fang F

Frontiers in microbiology 20190109

Rabbit hemorrhagic disease (RHD) is a highly contagious disease caused by rabbit hemorrhagic disease virus (RHDV). Previous research has shown that RHDV induces apoptosis in numerous cell types, although the molecular mechanisms underlying the apoptosis induced by RHDV are not well understood. One possible factor is non-structural protein 6 (NSP6), a 3C-like protease that plays an important role in processing viral polyprotein precursors into mature non-structural proteins. To fully establish a ...[more]

PMID: 30687286

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Project description:BACKGROUND:Rabbit Hemorrhagic Disease Virus (RHDV) belongs to the Caliciviridae family, is a highly lethal pathogen to rabbits. Increasing numbers of studies have demonstrated the existence of antigenic variation in RHDV, leading to the emergence of a new RHDV isolate (RHDVb). However, the underlying factors determining the emergence of the new RHDV and its unpredictable epidemiology remain unclear. To investigate these issues, we selected more than 184 partial and/or complete genome sequences of RHDV from GenBank and analyzed their phylogenetic relationships, divergence, and predicted protein modification sites. RESULTS:Phylogenetic analysis showed that classic RHDV isolates, RHDVa, and RHDVb formed different clades. It's interesting to note that RHDVa being more closely related to classic RHDV than RHDVb, while RHDVb had a closer genetic relationship to Rabbit Calicivirus (RCV) than to classic RHDV isolates. Moreover, divergence analysis suggested that the accumulation of amino acid (aa) changes might be a consequence of adaptive diversification of capsid protein (VP60) during the division between classical RHDV, RHDVa, RHDVb, and RCV. Notably, the prediction of N-glycosylation sites suggested that RHDVb subtypes had two unique N-glycosylation sites (aa 301, 362) but lacked three other N-glycosylation sites (aa 45, 308, 474) displayed in classic RHDV and RHDVa VP60 implying this divergence of N-glycosylation sites in RHDV might affect viral virulence. Analysis of phosphorylation sites also indicated that some phosphorylation sites in RHDVa and RHDVb differed from those in classic RHDV, potentially related to antigenic variation in RHDV. CONCLUSION:The genetic relationship between RHDVb and RCV was closer than classic RHDV isolates. Moreover, compared to RHDV and RHDVa, RHDVb had two unique N-glycosylation sites but lacked three sites, which might affect the virulence of RHDV. These results may provide new clues for further investigations of the origin of new types of RHDV and the mechanisms of genetic variation in RHDV.

Project description:Rabbit hemorrhagic disease virus (RHDV) is a member of the Caliciviridae family (Lagovirus genus). RHDV is highly contagious and attaches to epithelial cells in the digestive or respiratory tract, leading to massive lesions with high mortality rates. A new variant of RHDV (termed RHDVb) recently has emerged, and previously vaccinated rabbits appear to have little protection against this new strain. Similar to human norovirus (Caliciviridae, Norovirus genus), RHDV binds histo-blood group antigens (HBGAs), and this is thought to be important for infection. Here, we report the HBGA binding site on the RHDVb capsid-protruding domain (P domain) using X-ray crystallography. The HBGA binding pocket was located in a negatively charged patch on the side of the P domain and at a dimeric interface. Residues from both monomers contributed to the HBGA binding and involved a network of direct hydrogen bonds and water-mediated interactions. An amino acid sequence alignment of different RHDV strains indicated that the residues directly interacting with the ABH-fucose of the HBGAs (Asp472, Asn474, and Ser479) were highly conserved. This result suggested that different RHDV strains also could bind HBGAs at the equivalent pocket. Moreover, several HBGA binding characteristics between RHDVb and human genogroup II norovirus were similar, which indicated a possible convergent evolution of HBGA binding interactions. Further structural studies with other RHDV strains are needed in order to better understand the HBGA binding mechanisms among the diverse RHDV strains.We identified, for the first time, the HBGA binding site on an RHDVb P domain using X-ray crystallography. Our results showed that RHDVb and human genogroup II noroviruses had similar HBGA binding interactions. Recently, it was discovered that synthetic HBGAs or HBGA-expressing enteric bacteria could enhance human genogroup II norovirus infection in B cells. Considering that RHDVb and genogroup II norovirus similarly interacted with HBGAs, it may be possible that a comparable cell culture system also could work with RHDVb. Taken together, these new findings will extend our understanding of calicivirus HBGA interactions and may help to elucidate the specific roles of HBGAs in calicivirus infections.

Dataset Information

Rabbit Hemorrhagic Disease Virus Non-structural Protein 6 Induces Apoptosis in Rabbit Kidney Cells.

Publications

Rabbit Hemorrhagic Disease Virus Non-structural Protein 6 Induces Apoptosis in Rabbit Kidney Cells.

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