Research Groups
Mammalian Biology: Virology
Research Interests and Description
Staff Research Scientist: Sunil Kumar Lal, PhD
Group Leader: Shahid Jameel
Research Interests
Host-virus relationships at the protein-protein interaction level for respiratory viruses. Avian Influenza and SARS.
Description of Research
SARS coronavirus
Since the outbreak of the SARS epidemic in South-East Asia, we have focused on the molecular biology of the SARS-CoV. To date, we have studied the Nucleocapsid (N) protein of the SARS-CoV and its ability to self-associate, induce apoptosis and actin reorganization in mammalian cells under stress, be phosphorylated by the cyclin-CDK complex and deregulate the cell-cycle. The SARS-CoV accessory protein 3a has been shown to interact with the spike, envelope and membrane glycoprotein, and has recently been established to be a structural component of the capsid. We have studied its RNA binding activities and shown that the central 75 amino-acid region of the 3a accessory protein was capable of binding specifically to the 5' untranslated region (5'UTR) of the SARS virus genomic RNA. 3b also induces AP-1 transcriptional activity through activation of JNK and ERK pathways. We have shown that the 7a accessory protein of SARS-CoV acts as a RNA silencing suppressor in host cells. This may have an important role in viral pathogenesis. We have also studied the 9b accessory protein and have recently shown that it diffuses into the nucleus, undergoes active crm1 mediated nucleocytoplasmic export and triggers apoptosis when retained in the nucleus.
Human Influenza A virus
(a) Innate host defense mechanisms: Double-stranded RNA dependent protein kinase (PKR) is a key regulator of the anti-viral innate immune response in mammalian cells. In case of influenza A virus (IAV) infection, P58IPK (the cellular inhibitor of PKR) is known to be released from HSP40 and inhibit PKR activation and concomitant eIF2α phosphorylation; however the role of influenza viral proteins aiding this release and the molecular mechanism is unknown. We discovered that influenza A virus nucleoprotein (NP) interacts with HSP40, and is responsible for P58IPK release, which in turn leads to downregulation of PKR and eIF2α phosphorylation. This mechanism is conserved across multiple influenza A virus strains including the 2009 H1N1 pandemic influenza virus. The expression of NP coincides with the dissociation of P58IPK from HSP40 with concomitant downregulation of p-PKR and p-eIF2α. Downregulation of NP expression in influenza virus infected cells restores p-PKR and p-eIF2α to normal levels. Our findings demonstrate a novel role of IAV NP in inhibiting PKR mediated anti-viral host response that ensures continued viral mRNA translation.
(b) Host cell survival pathway activation: Infection by influenza virus results in the activation of diverse cellular signalling pathways, which facilitate virus entry and replication. Infection also results in the phosphorylation of a number of cell signaling pathways. Activation of Akt plays a major role in modulating diverse downstream signaling pathways followed by cell survival, proliferation, migration, differentiation and apoptosis. Also, influenza virus induces the expression of adhesion molecules on the host cell surface. These adhesion molecules serve as co-receptors for virus infection. The neuraminidase (NA) protein is involved in virus release however, we have recently discovered that NA also enhances cell survival by activating the Akt pathway via Src signaling and directly interacting with the host CEACAM6 (carcinoembryonic cell adhesion molecule).
Recent Publications
Sharma, K., Ackerstorm, S., Sharma, A.K., Chow, V.K., Teow, S., Abrenica, B., Booth, S.A., Booth, T.F., Mirazimi, A., Lal, S.K. 2011. SARS-CoV 9b protein diffuses into nucleus, undergoes active crm1 mediated nucleocytoplasmic export and triggers apoptosis when retained in the nucleus. PLoS ONE 6, e19436 PubMed link
Sharma, K., Tripathi, S., Ranjan, P., Kumar, P., Garten, R., Deyde, V., Katz, J.M., Cox, N.J., Lal, R.B., Sambhara, S., Lal, S. K. 2011. Influenza A Virus Nucleoprotein Exploits Hsp40 to Inhibit PKR Activation. PLoS ONE 6, e20215 PubMed link
Karjee, S., Minhas, A., Sood, V., Ponia, S.S., Banerjea, A.C., Chow, V.T.K., Mukherjee, S.K., Lal, S.K. 2010. The 7a accessory protein of SARS-CoV acts as a RNA silencing suppressor. J Virol 84, 10395-10401 PubMed link
Surjit, M., Jameel, S., Lal, S.K. 2007. Cytoplasmic localization of the ORF2 protein of hepatitis E virus is dependent on its ability to undergo retrotranslocation from the endoplasmic reticulum. J Virol 81, 3339-3345 PubMed link
Surjit, M., Liu, B., Chow, V.T.K., Lal, S.K. 2006. The Nucleocapsid protein of SARS-coronavirus inhibits the activity of cyclin-CDK complex and blocks S phase progression in mammalian cells. J Biol Chem 281, 10669-10681 PubMed link
Surjit, M., Kumar, R., Mishra, R. N., Reddy, M. K., Chow, V. T. K., Lal, S. K. 2005. The SARS coronavirus nucleocapsid protein is phosphorylated and localizes in the cytoplasm by 14-3-3 mediated translocation. J Virol 79, 11476-11486 PubMed link
