Identification and Characterization of Rab39a and Its Role in Crosspresentation
Authors
Cruz, Freidrich M.Faculty Advisor
Kenneth L. Rock, Ph.D.Academic Program
Immunology and MicrobiologyUMass Chan Affiliations
PathologyDocument Type
Doctoral DissertationPublication Date
2017-05-31Keywords
Antigen PresentationDendritic Cell
Rab GTPase
Crosspresentation
MHC
Cell Biology
Immunity
Immunology of Infectious Disease
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Crosspresentation 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.DOI
10.13028/M2GG6KPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32277Related Resources
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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http://creativecommons.org/licenses/by-nc/4.0/ae974a485f413a2113503eed53cd6c53
10.13028/M2GG6K
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