Harvard Medical School


Contact Information:

Harvard Medical School

77 Avenue Louis Pasteur

NRB-830

Boston, MA 02115


Phone: 617-432-1978
Fax: 617-432-2789

dorf@hms.harvard.edu

Division of Immunology

 

Research Summary

Our laboratory studies the molecular mechanisms which regulate innate immune responses. The innate immune system senses invading microbial pathogens and plays an essential role in host defense. Through biochemical, genetic and computational approaches we examine the circuit of protein-protein interactions that signal antiviral responses. In addition, we investigate the signaling mechanisms which control production of antiviral and inflammatory cytokines.

Specific research interests:
1) Proteomic analysis of the human innate immune interactome for type I interferon production. We follow the dynamic changes in protein-protein interactions resulting from encounter with microbial ligands. Using proteomic strategies new components of signaling modules are defined and novel proteins are examined for antiviral activity. The data are integrated to define a comprehensive antiviral innate immune network.
2) Biochemical and functional analysis of TBK1, the central kinase for production of type I interferons. Studies of TBK1 posttranslational modification, recruitment, substrate interaction, and catalytic activation are conducted. The importance of TBK1 to antiviral immunity is underscored by observations that several viruses evolved strategies to subvert this signaling pathway. Thus, we also seek to provide a mechanistic understanding of how virus-host protein interactions remodel the interactome or inhibit TBK1 catalytic activity and interferon production.
3) Role of ubiquitylation in regulation of innate immune signaling pathways. The proteome can be remodeled by addition of polyubiquitin to meet environmental challenges. The isopeptide bond between ubiquitin groups contributes to protein fate, i.e. degradation or stabilization. We investigate the role of E3 ubiquitin ligases in assembly of signalosomes and signal transmission.

Selected Publications

Li, S., L. Wang, M.A. Berman, and M.E. Dorf. 2006. RNAi screen in mouse astrocytes identifies phosphatases that regulate NF-kB signaling. Mol. Cell 24:497-509.

Li, S., L. Wang, and M.E. Dorf. 2009. PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination. Mol. Cell 33:30-42.

Li, S., L. Wang, M. Berman, Y-Y. Kong, and M.E. Dorf. 2011. Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 35, 426-440.