BBS Faculty Member - Michaela Gack

Michaela Gack

Department of Microbiology and Immunobiology

Harvard Medical School
NRB Building, Room 930E
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-432-2378
Fax: 617-432-4787
Email: michaela_gack@hms.harvard.edu
Visit my lab page here.



Understanding host-viral interaction is an essential step in developing safe and effective antimicrobials against biodefense agents and emerging pathogens. The early detection of invading viruses by the host depends on a limited number of specific receptors that detect viral patterns and activate signaling cascades, thereby triggering interferon (IFN)-mediated antiviral defense mechanisms. Retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) have emerged as key cytosolic receptors for sensing RNA viruses including paramyxoviruses, influenza virus, Flaviviruses and picornaviruses. In addition, members of the tripartite motif (TRIM) protein family play a major role in the inhibition of virus lifecycles.

I) Regulation of RIG-I/MDA5-mediated antiviral innate immunity by host factors. Using molecular, biochemical and cell biological approaches, we are identifying and characterizing the regulatory mechanisms that govern the detection of RNA viruses through the cytosolic receptors RIG-I and MDA5 and the subsequent induction of signaling cascades leading to IFN-α/β gene expression. Our previous work demonstrated that the interconnection between RIG-I and a member of the TRIM protein family represents a novel class of regulatory pathway in innate immunity. Specifically, we showed that RIG-I undergoes Lys 63-linked ubiquitination induced by TRIM25 ubiquitin E3 ligase, enabling RIG-I to induce antiviral IFN induction. Ongoing studies are focused on identifying and characterizing novel host factors that play key roles in the regulation of the RIG-I/TRIM25 or MDA5 signaling pathway.

II) Viral evasion of the innate immune response. Among the virus-host interactions that modulate pathogenesis, the virus-mediated induction and inhibition of the type I IFN system play a critical role. Our studies revealed that the non-structural protein 1 (NS1) of human, swine and avian influenza A viruses interacts with and inhibits TRIM25, resulting in the abolished RIG-I ubiquitination and host antiviral IFN response. These findings unveiled a novel immune evasion mechanism of influenza A virus and also emphasized the vital role of TRIM25 in modulating viral infections. We are now determining the precise mechanism by which influenza NS1 inhibits TRIM25, and how sequence variations in TRIM25 of different species influence the NS1-TRIM25 interaction. Furthermore, our current studies are focused on the identification of novel viral factors that modulate the host antiviral interferon response.

III) The role of TRIM proteins in antiviral defense. In the past few years, it has become evident that the TRIM protein family represents a new class of antiviral molecules. However, the precise mechanisms by which TRIM proteins inhibit viral infections remain elusive. Research in my laboratory aims at identifying novel TRIM proteins that play key roles in innate immune responses to viral infections. We will further define the molecular mechanisms of antiviral TRIM proteins.



Last Update: 6/18/2014



Publications

For a complete listing of publications click here.

 


 

Gack, M.U., Shin, Y.C., Joo, C.H., Urano, T., Liang, C., Sun, L., Takeuchi, O., Akira, S., Chen, Z., Inoue, S., & Jung, J.U. (2007). TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916-920.

Gack, M.U., Kirchhofer, A., Shin, Y.C., Inn, K., Liang, C., Cui, S., Myong, S., Ha, T.K., Hopfner, K.P., & Jung, J.U. (2008). Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated anti-viral signal transduction.
Proc. Natl. Acad. Sci. U.S.A. 105(43):16743-8.

Gack, M.U., Albrecht, R.A., Urano, T., Inn, K., Huang, I.C., Carnero, E., Farzan, M., Inoue, S., Jung, J.U. & Garcia-Sastre, A. (2009). Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by RIG-I.
Cell Host Microbe. May 8;5(5):439-449.

Maharaj, N.P., Wies, E., Stoll, A., and Gack, M.U. (2012). Conventional protein kinase C-α (PKC-α) and PKC-β negatively regulate RIG-I antiviral signal transduction.
J Virol, 86(3):1358-71.

Rajsbaum, R., Albrecht, R.A., Maharaj, N.P., Wang, M.K., Versteeg, G.A., Nistal-Villán, E., García-Sastre, A., and Gack, M.U. (2012). Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.
PLoS Pathogens 2012 Nov;8(11):e1003059 PMID: 23209422

Wies, E., Wang, M.K., Maharaj, N.P., Chen, K., Zhou, S., Finberg, R. W., and Gack, M.U. (2013). Dephosphorylation of the RNA Sensors RIG-I and MDA5 by the Phosphatase PP1 Is Essential for Innate Immune Signaling.
Immunity 2013 Mar 12. doi:10.1016/j.immuni.2012.11.018. PMID: 23499489

Pauli, E.-K., Chan Y.K., Davis, M.E., Gableske, S., Wang, M.K., Feister, F.F., and Gack, M.U. (2014). The Ubiquitin-Specific Protease USP15 Promotes RIG-I-Mediated Antiviral Signaling by Deubiquitylating TRIM25.
Science Signaling 7, ra3 (2014).



© 2013 by the President and Fellows of Harvard College