Proteolytic Generation of Antigenic Peptides

Yewdell, J W.

Abstract

CD8 expressing T cells (T/CD8+ ) play a critical role in eradicating intracellular parasites such as viruses. T/CD8+ recognize MHC class I molecules in a complex with peptides of 8 to 10 residues derived from viral proteins located in the cytosol. There is tremendous interest in the mechanism by which peptides are generated. Indirect evidence implicates proteasomes in the generation of antigenic peptides. Proteasomes are abundant macromolecular structures present in the cytosol and nucleus, and have multiple protease activities. They are thought to be responsible for energy dependent proteolysis in which ubiquitin plays a prominent role in targeting proteins for destruction. In this project we examine the contribution of proteasomes to the production of antigenic peptides and also explore the nature of substrates acted on by cytosolic peptidogenic proteases. Another goal is to identify sequences that enhance the immunogenicity of proteins by increasing their capacity to generate antigenic peptides.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000658-06
• Application #: 6160685
• Study Section: Special Emphasis Panel (LVD)
• Support Year: 6
• Fiscal Year: 1997

Institution

• Name: National Institute of Allergy and Infectious Diseases
• Country: United States

Publications

Lev, Avital; Takeda, Kazuyo; Zanker, Damien et al. (2008) The exception that reinforces the rule: crosspriming by cytosolic peptides that escape degradation. Immunity 28:787-98

Yewdell, Jonathan W; Lev, Avital (2007) Self-reporting peptides illuminate the MHC groove. Nat Chem Biol 3:201-2

Pruszczyk, Piotr; Kostera-Pruszczyk, Anna; Shatunov, Alexey et al. (2007) Restrictive cardiomyopathy with atrioventricular conduction block resulting from a desmin mutation. Int J Cardiol 117:244-53

Tscharke, David C; Woo, Wai-Ping; Sakala, Isaac G et al. (2006) Poxvirus CD8+ T-cell determinants and cross-reactivity in BALB/c mice. J Virol 80:6318-23

Pasquetto, Valerie; Bui, Huynh-Hoa; Giannino, Rielle et al. (2005) HLA-A*0201, HLA-A*1101, and HLA-B*0702 transgenic mice recognize numerous poxvirus determinants from a wide variety of viral gene products. J Immunol 175:5504-15

Oseroff, Carla; Kos, Ferdynand; Bui, Huynh-Hoa et al. (2005) HLA class I-restricted responses to vaccinia recognize a broad array of proteins mainly involved in virulence and viral gene regulation. Proc Natl Acad Sci U S A 102:13980-5

Chanturiya, A N; Basanez, G; Schubert, U et al. (2004) PB1-F2, an influenza A virus-encoded proapoptotic mitochondrial protein, creates variably sized pores in planar lipid membranes. J Virol 78:6304-12

Ott, David E; Coren, Lori V; Sowder 2nd, Raymond C et al. (2003) Retroviruses have differing requirements for proteasome function in the budding process. J Virol 77:3384-93

Houde, Mathieu; Bertholet, Sylvie; Gagnon, Etienne et al. (2003) Phagosomes are competent organelles for antigen cross-presentation. Nature 425:402-6

Eriksson, Maria; Brown, W Ted; Gordon, Leslie B et al. (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293-8