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Dissertation
Ubiquitin plays a critical role in hepatitis B virus envelope proteins MHC class I antigen presentation
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2011
DOI:
https://doi.org/10.17918/00009490
Abstract
Hepatitis B virus envelope glycoproteins Large (L), Middle (M) and Small (S) are targets of the host cellular immune system. The extent to which the host recognizes viral antigens presented by infected cells is believed to play a decisive role in determining if an infection will be resolved or become chronic. As with other antigens, HBV envelope polypeptides must be degraded, presumably by cellular proteasomes, to be presented by the MHC class I pathway. The M protein, which behaves like the S protein in protein folding and secretion, was used as a model to study this process and determine how ER quality control machinery monitors foreign polymeric proteins and disposes of them through the ER-associated degradation (ERAD) pathway. We found that unlike most ERAD substrates, which require ubiquitination for retrotranslocation and degradation, the HBV M protein, which only contains two lysine residues, can undergo rapid and complete, ubiquitin-independent, proteasome-dependent degradation. The utilization of this pathway has a functional consequence, since proteins degraded through it are poorly presented via MHC I. Interestingly, when the level of ubiquitination was increased through the insertion of additional lysine residues, the level of antigen presentation was significantly enhanced without altering the rate of protein degradation. This result indicates that the 11BV M and S proteins can utilize an ubiquitin-independent ERAD pathway to limit class I antigen presentation. In contrast, the HBV L protein, which includes the entire M and S domains and contains two additional lysine residues in its N-terminal preS1 domain, requires ubiquitination for its proteasomal degradation and subsequent antigen presentation. This result implies that during infection, the HBV L protein, but not the M or S proteins, is targeted for ubiquitin-dependent degradation and contributes to the class I antigen presentation of HBV envelope proteins. In conclusion, using HBV envelope proteins as a model, we have identified a novel ubiquitinin-dependent degradation pathway and determined that this pathway can have implications for antigen presentation and potentially viral pathogenesis.
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Details
- Title
- Ubiquitin plays a critical role in hepatitis B virus envelope proteins MHC class I antigen presentation
- Creators
- Yuanjie Liu
- Contributors
- Anand S. Mehta (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 164 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021889062604721