Journal
CELL
Volume 158, Issue 3, Pages 506-521Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.04.054
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Funding
- NIH [5R24 CA095823-04, S10 RR0 9145-01, AI073899, HL56652, HL082193, AI104848, CA154649, DK072201, AI095245]
- NSF [DBI-9724504]
- German Research Foundation-Membrane Transport and Communication [SFB 807, TA157/7]
- Landsteiner Foundation for Blood Research
- Dutch Organization for Science
- Burroughs Wellcome Fund
- American Cancer Society [117254]
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Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly understood. Here, we show that MHC-I selectively accumulate within phagosomes carrying microbial components, which engage Toll-like receptor (TLR) signaling. Although cross-presentation requires Sec22b-mediated phagosomal recruitment of the peptide loading complex from the ER-Golgi intermediate compartment (ERGIC), this step is independent of TLR signaling and does not deliver MHC-I. Instead, MHC-I are recruited from an endosomal recycling compartment (ERC), which is marked by Rab11a, VAMP3/cellubrevin, and VAMP8/endobrevin and holds large reserves of MHC-I. While Rab11a activity stocks ERC stores with MHC-I, MyD88-dependent TLR signals drive I kappa B-kinase (IKK) 2-mediated phosphorylation of phagosome-associated SNAP23. Phospho-SNAP23 stabilizes SNARE complexes orchestrating ERC-phagosome fusion, enrichment of phagosomes with ERC-derived MHC-I, and subsequent cross-presentation during infection.
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