Antigen presentation by MHC class II is critical for immune responses against pathogens and tumors. Antigen loading occurs primarily in lysosomal-related organelles (LROs) known as MIICs.... Show moreAntigen presentation by MHC class II is critical for immune responses against pathogens and tumors. Antigen loading occurs primarily in lysosomal-related organelles (LROs) known as MIICs. Ultimately, the MHC II-peptide complexes are transported for cell surface display. Here, we study intracellular transport of MIICs, a poorly understood process in MHC II antigen presentation. We propose that Rab7 lies at the heart of transport by assembling a specific receptor (Rab7-RILP-ORP1L) for the minus end-directed dynein-dynactin motor on the cytosolic face of MIICs/LROs. Full activation of transport requires a second receptor, _III spectrin. Whereas this model explains how Rab7 controls minus end-directed transport, it does not suffice to explain the characteristic pattern of bidirectional motility exhibited by MIICs/LROs. Here, we propose that cholesterol dictates ORP1L conformation which acts as a switch controlling access of dynein-dynactin to Rab7-RILP, thereby regulating LRO positioning, as observed in NPC disease. Rab7-RILP-ORP1L may also integrate transport and tethering of MIICs/LROs, consecutive processes within the endocytic pathway. Show less
