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* Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
Department of Medicine, Harvard Medical School, Boston, MA 02115;
Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;
CBR Institute for Biomedical Research, Boston, MA 02115; and
¶ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
Immature dendritic cells (DCs) capture exogenous Ags in the periphery for eventual processing in endolysosomes. Upon maturation by TLR agonists, DCs deliver peptide-loaded class II MHC molecules from these compartments to the cell surface via long tubular structures (endolysosomal tubules). The nature and rules that govern the movement of these DC compartments are unknown. In this study, we demonstrate that the tubules contain multiple proteins including the class II MHC molecules and LAMP1, a lysosomal resident protein, as well as CD63 and CD82, members of the tetraspanin family. Endolysosomal tubules can be stained with acidotropic dyes, indicating that they are extensions of lysosomes. However, the proper trafficking of class II MHC molecules themselves is not necessary for endolysosomal tubule formation. DCs lacking MyD88 can also form endolysosomal tubules, demonstrating that MyD88-dependent TLR activation is not necessary for the formation of this compartment. Endolysosomal tubules in DCs exhibit dynamic and saltatory movement, including bidirectional travel. Measured velocities are consistent with motor-based movement along microtubules. Indeed, nocodazole causes the collapse of endolysosomal tubules. In addition to its association with microtubules, endolysosomal tubules follow the plus ends of microtubules as visualized in primary DCs expressing end binding protein 1 (EB1)-enhanced GFP.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded in part by the Ellison Medical Foundation Global Infectious Disease Program (to J.V.), the Pfizer Fellowship in Infectious Diseases (to J.V.), and the National Institutes of Health K08 (5K08AI057999). Y.M.K. was a fellow of the Leukemia and Lymphoma Society. K.A.T. is a National Institutes of Health National Research Service Award fellow (1F32CA105862-01). J.C.L. is a Gilead Fellow of Life Sciences Research Foundation. H.L.P. is supported by the National Institutes of Health (5R01AI034893-13).
2 Address correspondence and reprint requests to Dr. Jatin M. Vyas, Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142. E-mail address: jvyas{at}partners.org
3 Abbreviations used in this paper: DC, dendritic cells; CN, Cryptococcus neoformans; BM, bone marrow, BMDC, BM-derived DC; EB1, end binding protein 1; eGFP, enhanced GFP; ER, endoplasmic reticulum; LAMP1, lysosomal-associated membrane protein 1; mRFP1, monomeric red fluorescent protein 1; YFP, yellow fluorescent protein.
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