The Selective Inhibition of Host Cell mRNA Export by Kaposi’s Sarcoma-Associated Herpesvirus

One of the major important processes that eukaryotes undergo is nuclear mRNA export, which is responsible for bringing the host cell’s RNA-encoded genetic information into the cytoplasm in order for it to be translated into proteins. This export is a critical for gene expression, as the number and type of mRNAs that are successfully translated directly affects levels and types of proteins produced. As such, it comes as no surprise that this process is substantially regulated by the host cell, in order to ensure efficient and accurate gene expression. These regulations can occur at various time points during the mRNAs’ lifetime, including during the pre-mRNA stage, where early transcripts are developed and converted into mature mRNAs, or during the export process itself, which can involve various different nuclear export factors and machinery for proper movement.¹

Many viruses, in order to combat the expression of host cell immune response and defense genes, can inhibit this nuclear export to some degree through their viral proteins, including, notably, influenza virus.² Another well-understood example of this is the matrix protein M of vesicular stomatitis virus (VSV), which broadly inhibits mRNA export by preventing a certain nuclear export factor complex, Rae1-Nup98, from interacting with the transcripts.³ In a paper by Gong et al. that was recently published in Cell Host & Microbe, researchers discovered the first example of transcript-selective, rather than nonspecific, inhibition, that is regulated by the open reading frame 10 (ORF10) protein of Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV is a type of gamma herpesvirus, which are large DNA viruses that commonly manipulate cellular mRNA machinery in order to boost the efficiency of their viral replication.³ Unlike the prior examples of viruses that inhibit host cell mRNA export globally, such as that seen with the M protein of VSV, KSHV does not affect all mRNAs. While KSHV still does involve the export factor complex Rae1-Nup98, it instead functions to inhibit the movement of only those transcripts containing specific sequence elements in their 3’ untranslated region (UTR).³ In this way, KSHV can selectively block target host cell mRNAs from nuclear export, while still allowing for the proper movement of any other necessary mRNAs, such those encoded by the virus for the purpose of replication or infection. Interestingly, rather than preventing nuclear export by blocking the Rae1-Nup98 complex from binding to the mRNAs, the ORF10 protein of KSHV instead binds to this complex itself, inactivating the export process through this interaction.³

Figure 1: siRNA knockdown, a method used to decrease the expression of target gene, was used against Rae1 or its binding complex partner Nup98. Knockdown of either binding partner results in the export of ORF10 (green) outside of the host cell nucleus, indicating that ORF10 requires the presence of this binding complex in order to remain in the nucleus and consequently prevent mRNA nuclear export.³

Ultimately, this newly discovered form of mRNA nuclear export inhibition by KSHV expands the potential for viruses to counter host cell responses to viral infections. While inhibition of mRNA export has been seen previously on a global level by VSV and other viruses, this mRNA-selective method allows for KSHV to block host cell mRNAs, such as those coding for immune responses, without blocking the expression of the virally-encoded transcripts that are required for efficient viral replication. For this reason, this study provides an interesting factor in ORF10 for further research, as a knockdown of this protein may mitigate the success of KSHV in humans, potentially blocking its counter-immune inhibition of the host cell’s mRNA nuclear export.  Overall, viruses have a broad range of ways to combat and inactivate host cell responses, and this research by Gong et al. provides new insight into one such process undergone by Kaposi’s sarcoma-associated herpesvirus.

References:

1 Darzacq, X., Singer, R.H., Shav-Tal, Y. (2005). Dynamics of transcription and mRNA export. Current Opinion in Cell Biology 17: 239-342.

2 Yarbrough, M.L., Mata, M.A., Sakthivel, R., and Fontoura, B.M.A. (2014). Viral subversion of nucleocytoplasmic trafficking. Traffic 15: 127–140.

3 Gong, D., Kim, Y.H., Xiao, Y., Du, Y., Xie, Y., Lee, K.K., Feng, J., Farhat, N., Zhao, D., Shu, S., Dai, X., Chanda, S.K., Rana, T.R., Krogan, N.J., Sun, R., Wu, T. (2016). A Herpesvirus Protein Selectively Inhibits Cellular mRNA Nuclear Export. Cell Host & Microbe 20: 642-653.