scholarly journals Inclusion Body Fusion of Human Parainfluenza Virus Type 3 Regulated by Acetylated α-Tubulin Enhances Viral Replication

2016 ◽  
Vol 91 (3) ◽  
Author(s):  
Shengwei Zhang ◽  
Yanliang Jiang ◽  
Qi Cheng ◽  
Yi Zhong ◽  
Yali Qin ◽  
...  
Keyword(s):  
Viral Replication ◽  
Virus Type ◽  
Inclusion Bodies ◽  
Viral Proteins ◽  
Cellular Proteins ◽  
Parainfluenza Virus ◽  
Syncytial Virus ◽  
Human Parainfluenza Virus ◽  
Type 3 ◽  
Efficient Viral Replication

ABSTRACT Viral inclusion bodies (IBs), or replication factories, are unique structures generated by viral proteins together with some cellular proteins as a platform for efficient viral replication, but little is known about the mechanism underlying IB formation and fusion. Our previous study demonstrated that the interaction between the nucleoprotein (N) and phosphoprotein (P) of human parainfluenza virus type 3 (HPIV3), an enveloped virus with great medical impact, can form IBs. In this study, we found that small IBs can fuse with each other to form large IBs that enhance viral replication. Furthermore, we found that acetylated α-tubulin interacts with the N-P complex and colocalizes with IBs of HPIV3 but does not interact with the N-P complex of human respiratory syncytial virus or vesicular stomatitis virus and does not colocalize with IBs of human respiratory syncytial virus. Most importantly, enhancement of α-tubulin acetylation using the pharmacological inhibitor trichostatin A (TSA), RNA interference (RNAi) knockdown of the deacetylase enzymes histone deacetylase 6 (HDAC6) and sirtuin 2 (SIRT2), or expression of α-tubulin acetyltransferase 1 (α-TAT1) resulted in the fusion of small IBs into large IBs and effective viral replication. In contrast, suppression of acetylation of α-tubulin by overexpressing HDAC6 and SIRT2 profoundly inhibited the fusion of small IBs and viral replication. Our findings offer previously unidentified mechanistic insights into the regulation of viral IB fusion by acetylated α-tubulin, which is critical for viral replication. IMPORTANCE Inclusion bodies (IBs) are unique structures generated by viral proteins and some cellular proteins as a platform for efficient viral replication. Human parainfluenza virus type 3 (HPIV3) is a nonsegmented single-stranded RNA virus that mainly causes lower respiratory tract disease in infants and young children. However, no vaccines or antiviral drugs for HPIV3 are available. Therefore, understanding virus-host interactions and developing new antiviral strategies are increasingly important. Acetylation on lysine (K) 40 of α-tubulin is an evolutionarily conserved modification and plays an important role in many cellular processes, but its role in viral IB dynamics has not been fully explored. To our knowledge, our findings are the first to show that acetylated α-tubulin enhances viral replication by regulating HPIV3 IB fusion.

scholarly journals Inclusion bodies of human parainfluenza virus type 3 inhibit antiviral stress granule formation by shielding viral RNAs

2018 ◽  
Vol 14 (3) ◽  
pp. e1006948 ◽  
Author(s):  
Zhulong Hu ◽  
Yuang Wang ◽  
Qiaopeng Tang ◽  
Xiaodan Yang ◽  
Yali Qin ◽  
...  
Keyword(s):  
Virus Type ◽  
Inclusion Bodies ◽  
Stress Granule ◽  
Parainfluenza Virus ◽  
Granule Formation ◽  
Viral Rnas ◽  
Human Parainfluenza Virus ◽  
Type 3

scholarly journals Recombinant Bovine/Human Parainfluenza Virus Type 3 (B/HPIV3) Expressing the Respiratory Syncytial Virus (RSV) G and F Proteins Can Be Used To Achieve Simultaneous Mucosal Immunization against RSV and HPIV3

2001 ◽  
Vol 75 (10) ◽  
pp. 4594-4603 ◽  
Author(s):  
Alexander C. Schmidt ◽  
Josephine M. McAuliffe ◽  
Brian R. Murphy ◽  
Peter L. Collins
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Host Range ◽  
Virus Type ◽  
Serum Antibody ◽  
Parainfluenza Virus ◽  
Range Restriction ◽  
Syncytial Virus ◽  
Human Parainfluenza Virus ◽  
Type 3

ABSTRACT Recombinant bovine/human parainfluenza virus type 3 (rB/HPIV3), a recombinant bovine PIV3 (rBPIV3) in which the F and HN genes were replaced with their HPIV3 counterparts, was used to express the major protective antigens of respiratory syncytial virus (RSV) in order to create a bivalent mucosal vaccine against RSV and HPIV3. The attenuation of rB/HPIV3 is provided by the host range restriction of the BPIV3 backbone in primates. RSV G and F open reading frames (ORFs) were placed under the control of PIV3 transcription signals and inserted individually into the rB/HPIV3 genome in the promoter-proximal position preceding the nucleocapsid protein gene. The recombinant PIV3 expressing the RSV G ORF (rB/HPIV3-G1) was not restricted in its replication in vitro, whereas the virus expressing the RSV F ORF (rB/HPIV3-F1) was eightfold restricted compared to its rB/HPIV3 parent. Both viruses replicated efficiently in the respiratory tract of hamsters, and each induced RSV serum antibody titers similar to those induced by RSV infection and anti-HPIV3 titers similar to those induced by HPIV3 infection. Immunization of hamsters with rB/HPIV3-G1, rB/HPIV3-F1, or a combination of both viruses resulted in a high level of resistance to challenge with RSV or HPIV3 28 days later. These results describe a vaccine strategy that obviates the technical challenges associated with a live attenuated RSV vaccine, providing, against the two leading viral agents of pediatric respiratory tract disease, a bivalent vaccine whose attenuation phenotype is based on the extensive host range sequence differences of BPIV3.

scholarly journals Attenuation of the Recombinant Human Parainfluenza Virus Type 3 cp45 Candidate Vaccine Virus Is Augmented by Importation of the Respiratory Syncytial Virus cpts530 L Polymerase Mutation

Virology ◽  
1999 ◽  
Vol 260 (1) ◽  
pp. 125-135 ◽  
Author(s):  
Mario H. Skiadopoulos ◽  
Sonja R. Surman ◽  
Marisa St. Claire ◽  
William R. Elkins ◽  
Peter L. Collins ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Virus Type ◽  
Vaccine Virus ◽  
Candidate Vaccine ◽  
Parainfluenza Virus ◽  
Syncytial Virus ◽  
Human Parainfluenza Virus ◽  
Type 3

scholarly journals Interaction of Human Parainfluenza Virus Type 3 Nucleoprotein with Matrix Protein Mediates Internal Viral Protein Assembly

2015 ◽  
Vol 90 (5) ◽  
pp. 2306-2315 ◽  
Author(s):  
Guangyuan Zhang ◽  
Yi Zhong ◽  
Yali Qin ◽  
Mingzhou Chen
Keyword(s):  
Virus Type ◽  
Matrix Protein ◽  
Viral Proteins ◽  
Parainfluenza Virus ◽  
M Protein ◽  
Content Type ◽  
Virion Assembly ◽  
Nucleoprotein N ◽  
Human Parainfluenza Virus ◽  
Type 3

ABSTRACTHuman parainfluenza virus type 3 (HPIV3) belongs to theParamyxoviridaefamily. Its three internal viral proteins, the nucleoprotein (N), the phosphoprotein (P), and the polymerase (L), form the ribonucleoprotein (RNP) complex, which encapsidates the viral genome and associates with the matrix protein (M) for virion assembly. We previously showed that the M protein expressed alone is sufficient to assemble and release virus-like particles (VLPs) and a mutant with the L305A point mutation in the M protein (ML305A) has a VLP formation ability similar to that of wild-type M protein. In addition, recombinant HPIV3 (rHPIV3) containing the ML305Amutation (rHPIV3-ML305A) could be successfully recovered. In the present study, we found that the titer of rHPIV3-ML305Awas at least 10-fold lower than the titer of rHPIV3. Using VLP incorporation and coimmunoprecipitation assays, we found that VLPs expressing the M protein (M-VLPs) can efficiently incorporate N and P via an N-M or P-M interaction and ML305A-VLPs had an ability to incorporate P via a P-M interaction similar to that of M-VLPs but were unable to incorporate N and no longer interacted with N. Furthermore, we found that the incorporation of P into ML305A-VLPs but not M-VLPs was inhibited in the presence of N. In addition, we provide evidence that the C-terminal region of P is involved in its interaction with both N and M and N binding to the C-terminal region of P inhibits the incorporation of P into ML305A-VLPs. Our findings provide new molecular details to support the idea that the N-M interaction and not the P-M interaction is critical for packaging N and P into infectious viral particles.IMPORTANCEHuman parainfluenza virus type 3 (HPIV3) is a nonsegmented, negative-sense, single-stranded RNA virus that belongs to theParamyxoviridaefamily and can cause lower respiratory tract infections in infants and young children as well as elderly or immunocompromised individuals. However, no effective vaccine has been developed or licensed. We used virus-like particle (VLP) incorporation and coimmunoprecipitation assays to determine how the M protein assembles internal viral proteins. We demonstrate that both nucleoprotein (N) and phosphoprotein (P) can incorporate into M-VLPs and N inhibits the M-P interaction via the binding of N to the C terminus of P. We also provide additional evidence that the N-M interaction but not the P-M interaction is critical for the regulation of HPIV3 assembly. Our studies provide a more complete characterization of HPIV3 virion assembly and substantiation that N interaction with M regulates internal viral organization.

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