The GTPase Rab39a promotes phagosome maturation into MHC‐I antigen‐presenting compartments.

For CD8 T lymphocytes to mount responses to cancer and virally‐infected cells, dendritic cells must capture antigens present in tissues and display them as peptides bound to MHC‐I molecules. This is most often accomplished through a pathway called antigen cross‐presentation (XPT). Here, we report that the vesicular trafficking protein Rab39a is needed for optimal cross‐presentation by dendritic cells in vitro and cross‐priming of CD8 T cells in vivo. Without Rab39a, MHC‐I presentation of intraphagosomal peptides is inhibited, indicating that Rab39a converts phagosomes into peptide‐loading compartments. In this process, Rab39a promotes the delivery of MHC‐I molecules from the endoplasmic reticulum (ER) to phagosomes, and increases the levels of peptide‐empty MHC‐I conformers that can be loaded with peptide in this compartment. Rab39a also increases the levels of Sec22b and NOX2, previously recognized to participate in cross‐presentation, on phagosomes, thereby filling in a missing link into how phagosomes mature into cross‐presenting vesicles. Synopsis: Antigen cross‐presentation is essential for CD8 effector T‐cells to identify and eliminate cells that synthesize abnormal proteins due to mutations or viral infection. The small GTPase Rab39a stabilises phagosomal antigens and peptide‐empty MHC‐I molecules and promotes peptide loading of the latter, thus enhancing cross‐presentation by dendritic cells. Rab39a depletion decreases levels of peptide‐receptive MHC‐I molecules in the phagosomes.Rab39a loss increases phagosomal degradation of antigen and MHC‐I molecules.Rab39a boosts the level of NOX2 and Sec22 on the phagosome, thereby enhancing ROS accumulation and phagosome alkalinisation.Rab39a promotes the generation of peptide‐loaded MHC‐I complexes in phagosomes. [ABSTRACT FROM AUTHOR]