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Biodefense, Cell Biology, Cellular Immunity, Immunology, Infectious Disease, Membranes, Microarray, Protein Complexes, Protein Degradation, Protein Folding, Viruses and Virology
Multi-Disciplinary Training Areas
Immunology [IMM], Microbiology [MIC]
BS, Manhattan College
PhD, State University of New York at Stony Brook
Specific Clinical/Research Interest:
Viral subversion of the adaptive branch of the immune system
Current Students: Ph.D: Caroline Ng; Ph.D: Vanessa Noriega; Ph.D: Veronika Redmann
Postdoctoral Fellows: Kristina Oresic, Ph.D.
Research Personnel: Fatima Manzoor
Summary of Research Studies:
The immune system is alerted to the presence of a viral pathogen through the presentation of viral protein fragments (antigenic peptides) by the major histocompatibility complex (MHC) class I molecules. Selective pressure by the immune system on viruses has resulted in their ability to generate evasive tactics to avoid immune detection and become latent within the host. The main focus of the laboratory is to study how viruses evade immune detection. The human cytomegalovirus (HCMV), a member of the herpes virus family, can be used as a model to study strategies that viruses use to avoid the immune system by interfering with MHC class I antigen presentation. HCMV encodes a number of proteins derived from the unique short (US) region of the HCMV genome referred to as US2, US3, US6 and US11 that prevent the surface expression of Class I molecules. The US3 and US6 gene products interfere with Class I trafficking to the cell surface and loading of antigenic peptides into the Cla! ss I complex, respectively. US2 and US11 target the class I molecules for destruction by the proteasome. HCMV US2 and US11 induce the transport of the MHC class I molecules from the endoplasmic reticulum (ER) to the cytoplasm where it is degraded by the proteasome. US2 and US11 appear to have co-opted a cellular process to selectively eliminate class I molecules. This mode of destruction of ER proteins, also referred to as ER quality control, now is a more general process intended to dispose of misfolded (i.e. mutant version of the CFTR chloride conductance channel) and aberrant proteins.
The laboratory will focus on understanding how HCMV US2 and US11 target MHC class I for destruction. This includes defining the steps of the degradation process and identifying the cellular proteins involved in the pathway. The understanding of the dislocation process may lead to the development of pharmacological therapies against HCMV infection as well as other quality control related dis! eases. The laboratory will also concentrate on the identification of viral proteins from other latent viruses such as Varicella-Zoster virus and hepatitis B virus that interfere with the adaptive branch of the immune system. The manner in which these viral proteins function may help explain viral pathogenesis and may possibly elucidate cellular processes. Toxin proteins such as ricin toxin, Pseudomonas aeruginosa exotoxin A and cholera toxin bind to the cell surface and are transported to the ER lumen. Once in the ER, the toxins are translocated from the ER lumen to the cytosol where they disrupt normal cellular function. The laboratory will directly examine how these toxins are transported from the ER to the cytosol. Even though toxin translocation across the ER membrane and US2-and US11-mediated class I dislocation utilize a similar set of reactions, the protein complexes involved in the respective processes are likely to be diverse. The identification of the proteins involved in ER dislocation may be potential targets of pharmaceutical agents against toxin infection and dislocation-related diseases.
Oresic K, Ng C, Tortorella D. TRAM1 participates in HCMV US2- and US11-mediated dislocation of an ER membrane glycoprotein. J Biol Chem;: in press.
Oresic K, Mueller B, Tortorella D. Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome dependent manner. Biosci Rep;: in press.
Noriega VM, Tortorella D. Human cytomegalovirus-encoded immune modulators partner to down-regulate MHC class I molecules. J Virol; 83: 1359-1367.
Oresic K, Tortorella D. ER chaperones participate in HCMV US2-mediated degradation of class I MHC molecules. J Gen Virol 2008; 89: 1122-1130.
Noriega VM, Tortorella D. A bi-partite trigger for dislocation directs the proteasomal degradation of an ER membrane glycoprotein. J Biol Chem 2008; 283: 4031-4043.
Baker MB, Tortorella D. Dislocation of an ER membrane glycoprotein involves the formation of partially dislocated ubiquitinated polypeptides. J Biol Chem 2007; 282: 26845-26856.
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