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Title: | Influenza A virus infection-induced macroautophagy facilitates MHC class II-restricted endogenous presentation of an immunodominant viral epitope. | Austin Authors: | Deng, Jieru;Lu, Chunni;Liu, Chuanxin;Oveissi, Sara;Fairlie, Walter Douglas ;Lee, Erinna F;Bilsel, Pamuk;Puthalakath, Hamsa;Chen, Weisan | Affiliation: | Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia School of Cancer Medicine, La Trobe University, Melbourne, Vic., Australia Olivia Newton-John Cancer Research Institute School of Medicine, Deakin University, Waurn Ponds, Vic., Australia FluGen Inc., Madison, WI, USA |
Issue Date: | May-2021 | Date: | 2020-12-05 | Publication information: | The FEBS Journal 2021; 288(10): 3164-3185 | Abstract: | CD4+ T cells recognize peptides presented by major histocompatibility complex class II molecules (MHC-II). These peptides are generally derived from exogenous antigens. Macroautophagy has been reported to promote endogenous antigen presentation in viral infections. However, whether influenza A virus (IAV) infection-induced macroautophagy also leads to endogenous antigen presentation through MHC-II is still debated. In this study, we show that IAV infection leads to endogenous presentation of an immunodominant viral epitope NP311-325 by MHC-II to CD4+ T cells. Mechanistically, such MHC-II-restricted endogenous IAV antigen presentation requires de novo protein synthesis as it is inhibited by the protein synthesis inhibitor cycloheximide, and a functional ER-Golgi network as it is totally blocked by Brefeldin A. These results indicate that MHC-II-restricted endogenous IAV antigen presentation is dependent on de novo antigen and/or MHC-II synthesis, and transportation through the ER-Golgi network. Furthermore, such endogenous IAV antigen presentation by MHC-II is enhanced by TAP deficiency, indicating some antigenic peptides are of cytosolic origin. Most importantly, the bulk of such MHC-II-restricted endogenous IAV antigen presentation is blocked by autophagy inhibitors (3-MA and E64d) and deletion of autophagy-related genes, such as Beclin1 and Atg7. We have further demonstrated that in dendritic cells, IAV infection prevents autophagosome-lysosome fusion and promotes autophagosome fusion with MHC class II compartment (MIIC), which likely promotes endogenous IAV antigen presentation by MHC-II. Our results provide strong evidence that IAV infection-induced autophagosome formation facilitates endogenous IAV antigen presentation by MHC-II to CD4+ T cells. The implication for influenza vaccine design is discussed. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/26204 | DOI: | 10.1111/febs.15654 | ORCID: | 0000-0001-5178-1175 0000-0002-5221-9771 |
Journal: | The FEBS Journal | PubMed URL: | 33830641 | Type: | Journal Article | Subjects: | CD4+ T cell MHC‐II antigen presentation influenza A virus macroautophagy |
Appears in Collections: | Journal articles |
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