Molecular Mechanisms of MHC Class I-Antigen Processing: Redox Considerations

Abstract

Major histocompatibility complex (MHC) class I molecules present antigenic peptides to the cell surface for screening by CD8(+) T cells. A number of ER-resident chaperones assist the assembly of peptides onto MHC class I molecules, a process that can be divided into several steps. Early folding of the MHC class I heavy chain is followed by its association with beta(2)-microglobulin (beta(2)m). The MHC class I heavy chain-beta(2)m heterodimer is incorporated into the peptide-loading complex, leading to peptide loading, release of the peptide-filled MHC class I molecules from the peptide-loading complex, and exit of the complete MHC class I complex from the ER. Because proper antigen presentation is vital for normal immune responses, the assembly of MHC class I molecules requires tight regulation. Emerging evidence indicates that thiol-based redox regulation plays critical roles in MHC class I-restricted antigen processing and presentation, establishing an unexpected link between redox biology and antigen processing. We review the influences of redox regulation on antigen processing and presentation. Because redox signaling pathways are a rich source of validated drug targets, newly discovered redox biology-mediated mechanisms of antigen processing may facilitate the development of more selective and therapeutic drugs or vaccines against immune diseases.

In silico identification and analysis of the protein disulphide isomerases in wheat and rice

“…These observations strongly indicate that the cereal PDIL2 isoforms are strong candidates for being ER-based folding catalysts and/or chaperones. TaPDIL2-4 (reported as TaPDIL5-1, encoded by a gene located on 5L; d'Aloisio et al 2010) and OsPDIL2-3 were most similar to hP5 (Hayano & Kikuchi 1995), which possesses oxidase, isomerase and chaperone activities (Ellgaard & Ruddock 2005;Kim et al 2009). Interestingly, these two isoforms are also closely related to AtPDIL2-2 and AtPDIL2-3, which are involved in ER stress response (Kamauchi et al 2005;Lu & Christopher 2008a), and to GmPDIM, which physically associates with and plays chaperone roles in storage protein folding and is upregulated under ER stress and expressed in several tissues .…”

“…All PDIL5 exhibited only the a domain (Jeong et al 2008;Kim et al 2009) with two small insertions in OsPDIL5-4/OsPDIL5-4a. The active sites WCKHC or WCYWS are noted in some AtPDIL5s (Houston et al 2005), but their activites, especially of isoforms containing WCYWS, need investigation.…”

“…PDI is also a subunit of certain proteins, whereas PDILs have roles as components of peptide-loading complexes or in protein retention in the ER (Noiva 1999). PDI also functions in other cellular compartments or on the cell surface, and may function in cell-cell interactions (Noiva 1999;Kim et al 2009), transport of nitrous oxide (an intracellular signalling molecule) and estrogens (Sliskovic et al 2005;Fu et al 2008), activation of tissue factor (a major initiator of blood coagulation) (Manukyan et al 2008), and accumulation of misfolded proteins in neuro-degenerative diseases (Nakamura & Lipton 2009). It also has roles in apoptosis during ER stress caused by accumulation of misfolded proteins (Jeong et al 2008) and accelerating ERAD (ERassociated degradation) (Ushioda et al 2008).…”

Cytosolic Aminopeptidases Influence MHC Class I-Mediated Antigen Presentation in an Allele-Dependent Manner

“…Upon binding to an appropriate peptide, the MHC class I molecule is dissociated from the peptide-loading complex (PLC) that regulates optimal peptide loading into the MHC class I peptide-binding groove. The peptide-loaded MHC class I molecule is then transported to the cell surface, where it presents the bound peptide to CD8 ϩ T cells (2). Thus far, the fate of mature epitope precursors that are released from proteasomes into the cytosol remains unclear.…”

Roles of Cellular Redox Factors in Pathogen and Toxin Entry in the Endocytic Pathways

“…These include some intracellular bacterial and parasite pathogens that pass or live in the phagosomes, such as salmonella typhimurium, Mycobacterium tuberculosis, Leishmania spp and Trypanosoma cruzi. As a part of the protein folding machinery in the ER, PDI has been shown to directly regulate antigen processing of the MHC class I complex [64,65] .…”