Marlene Bouvier PhDProfessor
Our research activities are focused on the cell biology, immunology, and structural biology of class I major histocompatibility complex (MHC) molecules. Our projects share an unifying theme of better understanding the central role of class I MHC molecules in the immune system.
Class I MHC molecules bind short peptides, derived from the intracellular degradation of endogenous as well as viral or tumor-specific proteins, and present them at the cell surface for recognition by receptors on cytotoxic T-lymphocytes (CTLs). This cell-mediated recognition process is critically important to lyse infected or cancerous cells. The expression of class I MHC molecules at the surface of cells results from a complex series of molecular events initiated in the endoplasmic reticulum (ER) (Fig. 1). To mature efficiently in the ER, class I MHC molecules interact with several chaperones and accessory proteins including, calnexin, calreticulin, the thiol-dependent oxidoreductase ERp57, the transporter associated with antigen processing (TAP), and tapasin (TPN) (Fig. 1). Mature class I MHC molecules are transported via the Golgi complex to the cell surface. Overall, the class I assembly pathway is a critical intracellular process that ultimately controls the number of functional class I MHC molecules at the cell surface.
The folding of class I heavy chain is facilitated by the chaperonecalnexin and is followed by association with b2m. The class I heavy chain/b2m heterodimer is incorporated into a complex that comprises calreticulin, ERp57, TAP, and tapasin. Peptides derived from the cytosolic degradation of proteins are translocated into the ER by the two subunits of TAP. Mature class I MHC molecules are then transported through the Golgi complex and to the cell surface where peptides are presented to T-cell receptors.
Although our current understanding of how these proteins regulate class I assembly is far from complete, evidence suggest that they act in a coordinated manner to fold class I heavy chain, stabilize the class I heavy chain/b2m heterodimer, translocate peptides from the cytosol into the lumen of the ER, and influence the selection of antigenic peptides. Our laboratory is interested in studying molecular and structural aspects of the class I antigen presentation pathway. In recent years, we have characterized several of the proteins involved in this pathway using various biochemical and biophysical techniques. These efforts were aimed at better understanding the role and mode of action of these proteins within the class I assembly complex. More recently, we have proposed a molecular mechanism for how TPN influences the selection of antigens in the ER. This project is fundamental for linking the molecular cell biology of class I MHC molecules to fundamental aspects of protein interactions in the ER .
Given that the class I antigen presentation pathway is the first line of defense against viral infections and malignant transformations, it is not surprising that human viruses have evolved sophisticated strategies to downregulate the expression of class I MHC molecules at the cell surface and suppress the recognition of viral peptides by CTLs. Another area of interest in our laboratory is to study the molecular basis of viral immune evasion mechanisms that operate by interfering with the class I antigen presentation pathway. Currently, we are working with the immunomodulatory E3-19K protein from Adenovirus.
- Lenong Li
- Hui Deng
- Minae Kobayashi
- Structure of the Adenovirus Type 4 (Species E) E3-19K/HLA-A2 Complex Reveals Species-Specific... by Li L, Santarsiero BD, Bouvier M on January 1, 1970 at 12:00 am
Related ArticlesStructure of the Adenovirus Type 4 (Species E) E3-19K/HLA-A2 Complex Reveals Species-Specific Features in MHC Class I Recognition. J Immunol. 2016 Aug 15;197(4):1399-407 Authors: Li L, Santarsiero BD, Bouvier M Abstract Adenoviruses (Ads) subvert MHC class I Ag presentation and impair host anti-Ad cellular activities. Specifically, the Ad-encoded E3-19K immunomodulatory protein targets MHC class I molecules for retention within the […]