Molecular Cell & Developmental Biology
225 Sinsheimer Laboratories
Phone: 831.459.4986
Fax: 831.459.3139
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MARTHA ZÚÑIGA Professor of MCD Biology B. A., University of Texas at Austin Ph.D., Yale University ZÚÑIGA LAB

225 Sinsheimer Laboratories University of California Santa Cruz, CA 95064 phone 831.459.3180 fax 831.459.3139 zuñiga@biology.ucsc.edu office hours

The Zúñiga laboratory studies the cell biology of class I Major Histocompatibility Complex (MHC) molecules and its role in class I MHC function. These cell-surface glycoproteins alert the immune system to the presence of viruses within cells and also play an important role in the rejection of tissue grafts and tumors. The overall goals of the laboratory are to employ cell biological, immunological, and biophysical approaches to elucidate the role of class I MHC cell biology in the molecule's immunological function.

Regulation of Class I MHC Intracellular Transport
We have shown that cell-surface class I MHC molecules are internalized and transported back to the cell surface, passing through intracellular acidic compartments in transit. We also have found that the poxvirus, myxoma, interferes with class I MHC trafficking by targeting these molecules for degradation in an endolysosomal compartment, a fate which we believe is likely to be mediated by a recently identified myxoma virus gene product, MV-LAP. MV-LAP and the orthologous K5 protein of human herpesvirus-8, may bind directly to class I MHC or may exert their effects by influencing the activities of cellular proteins that regulate the cell-surface display and/or recycling of class I MHC molecule. For example, the tetraspan protein, EMP2, has recently been shown to increase the cell-surface expression of class I MHC. We will study the interactions of class I MHC with MV-LAP and with EMP2, as well as the interactions of MV-LAP with EMP2 to elucidate their roles in regulating class I MHC trafficking.

Regulation of the Dynamic Movement of Class I MHC on the Plasma Membrane
Interaction of cell-surface MHC molecules with antigen receptors (TCRs) on T lymphocytes involves their lateral movement on the plasma membrane into a specialized junction between the MHC-presenting cell and the T cell called the immunological synapse. Class I MHC movement into the immunological synapse may occur via Brownian motion or via regulated mechanisms. We and others have shown that the class I MHC cytoplasmic tail imposes constraints on class I MHC mobility. We now have applied single particle tracking methods and MHC mutants to study the role of the class I MHC cytoplasmic tail in MHC mobility on the membrane. Our studies indicate that both the sub-menbranous cytoskeleton and membrane domains, perhaps consisting of other cell-surface proteins, affect class I MHC diffusion. Ongoing work will determine if the cytoplasmic domain facilitates clustering into an immunological synapse, thus potentiating antigen presentation.

Functional Analysis of Class I MHC in the Establishment and Maintenance of Immunological Tolerance
To study the role of the membrane tether of the class I MHC molecule in MHC interaction with the TCR we are analyzing the function of a mutant class I MHC molecule with an altered membrane tether expressed in keratinocytes in a transgenic mouse model. We have found that T lymphocytes specific for this class I MHC molecule escape deletion in the thymus when the molecule is present in its mutant form. Skin grafts bearing the mutant class I MHC on skin are not rejected by mice transgenic for a TCR specific for that class I MHC molecule. Moreover, engraftment with such grafts can tolerize mice to skin grafts bearing normal class I MHC. The tolerated skin grafts are infiltrated with T lymphocytes. These results suggest that tolerance of skin grafts bearing the mutant class I MHC is due to the activity of regulatory T cells (Tregs) that inhibit the activity of otherwise active graft-specific T cells. We are in the process of testing this hypothesis further and are characterizing the infiltrates in tolerated skin grafts. These studies are clinically relevant in that Tregs have been demonstrated to attenuate the activity of tumor-specific T cells and to prevent autoimmune disease.

Selected Publications
Zúñiga, M. C. Lessons in Détente or Know thy Host: The Immunomodulatory Gene Products of Myxoma Virus. Biochemical Journal 28: 273-285 (2003).

Zúñiga, M. C. A Pox on Thee! Manipulation of the Host Immune System by Myxoma Virus and Implications for Viral-Host Co-Adaptation. Virus Research 88: 17-33 (2002).

Spiliotis, E.T., Osorio, M., Zúñiga, M.C., and Edidin, M. Selective Export of MHC Class I Molecules from the ER after their Dissociation from TAP. Immunity 13: 841-851 (2000.

Capps, G.G. and Zúñiga, M.C. Phosphorylation of Class I MHC Molecules in the Absence of Phorbol Esters is an Intracellular Event and May Be Characteristic of Trafficking Molecules. Molecular Immunology 37: 59-71 (2000).

Casagrande, R., Stern, P., Diehn, M., Shamu, C., Osorio, M., Zúñiga, M., Brown, P., and Ploegh, H. Degradation of Proteins from the ER Requires an Intact Unfolded Protein Response Pathway in S. cerevisiae. Molecular Cell. 5: 729-735 (2000).

Zúñiga, M.C., Wang, H., Barry, M., and McFadden, G. Endosomal/ Lysosomal Retention and Degradation of Major Histocompatibility Complex Class I Molecules Is Induced by Myxoma Virus. Virology 261: 180-192 (1999).