Identification and Characterization of Rab39a and Its Role in Crosspresentation
AuthorsCruz, Freidrich M.
Faculty AdvisorKenneth L. Rock, Ph.D.
Academic ProgramImmunology and Microbiology
UMass Chan AffiliationsPathology
Document TypeDoctoral Dissertation
Immunology of Infectious Disease
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AbstractCrosspresentation allows antigen presenting cells to present peptides from exogenously derived antigens onto MHC Class I for presentation to CD8+ T cells. Though this pathway shares key players with the Classical Class I and Class II pathways, several questions remain. A genomewide siRNA screen was performed to look for genes that selectively affected the crosspresentation or the Class II pathways. Among the genes identified in the screen was the Rab GTPase Rab39a. Rab39a was required for efficient crosspresentation but was dispensable for the presentation of endogenously expressed antigen. Both TAP-dependent and independent antigen required Rab39a for efficient presentation. Rab39a localized to late endosomes and phagosomes, though interestingly it was not required for the Class II pathway. Analysis of phagosomes from Rab39a KO or rescued cells has shown that in the presence of Rab39a, phagosomes were enriched for the open form of MHC Class I as well as TAP1, a member of the peptide loading complex. The enriched open form of MHC-I was peptide receptive, suggesting that it could contribute to crosspresentation. Phagosomes from Rab39a positive cells had reduced degradative capability and had increased levels of Sec22b, a SNARE protein reported to deliver ER-golgi sourced cargo to phagosomes. Furthermore, inhibition of ER-golgi transport via brefeldin A abolished the phenotype conferred by Rab39a. Thus, we hypothesize that Rab39a mediates the delivery of ER-golgi derived cargo to the antigen containing phagosome. This delivery allows peptide receptive MHC-I, as well as the peptide loading complex to reach the antigen, thereby facilitating crosspresentation.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32277
The original research presented in this dissertation is published in: Cruz FM, Colbert JD, Rock KL: The GTPase Rab39a promotes phagosome maturation into MHC-I antigen-presenting compartments. EMBO J 2019:e102020. https://doi.org/10.15252/embj.2019102020
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