Kaposi's Sarcoma associated Herpesvirus (KSHV) poses a serious threat to immunocompromised patients such as transplant recipients and AIDS patients. KSHV causes Kaposi's Sarcoma (KS), the most frequent cancer in HIV-infected patients, as well as other lymphoproliferative disorders. The virus has evolved means of subverting normal host immune defenses, allowing it to establish life-long infections. Our long-term goal is to fully understand how KSHV achieves this end. Such knowledge is not only critical to the understanding of KSHV pathogenesis, but also to the design of anti-viral drugs to treat patients at high risks for KS. We found that KSHV encodes two proteins, MIR1 and MIR2, that induce ubiquitination and subsequent internalization of the Major Histocompatibility Complex-I (MHC-I) molecules from the cell surface. This leads to the degradation of the MHC-I molecules thus preventing recognition of infected cells by the cytotoxic T lymphocytes (C'I-Ls). In this proposal, we aim at characterizing the molecular mechanisms implicated in the MIRl-induced downregulation of MHC-I molecules (specific aim 1 and 2). We recently discovered that MIR1 can downregulate MHC-I molecules independently of their lysine residues, the known targets of ubiquitination. We will test the hypothesis that, as suggested by our preliminary results, MIR1 can transfer ubiquitin to a cysteine residue, a completely novel and unexpected process (specific aim 1). An important step in our understanding of MIR1 functions will be to identify its cellular cofactors (specific aim 2).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108447-03
Application #
7073469
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2004-07-08
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$240,046
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704