The reverse logic of multivesicular endosomes

Fifty years after the first description of curious “multivesicular bodies” in micrographs of rat oocytes (Sotelo & Porter, 1959), it might seem odd that the precise mechanistic basis for the formation of these ubiquitous intracellular organelles remains as perplexing as their morphology. The biogenesis of multivesicular bodies (MVBs)—also known as late multivesicular endosomes—represents a subset of the remarkable endosomal transformations that occur in eukaryotic cells. Situated between early peripheral rab5 GTPase‐positive endosomes and the terminal lysosome compartment, MVBs are characterized by the presence of intralumenal vesicles (ILVs) and sometimes also onion‐like whorls of internal membrane (Fig 1). The internal packaging of the limiting membrane to generate ILVs is widely accepted to partition certain transmembrane molecules that were present originally at the cell surface into the MVB lumen. The spatial remodelling isolates receptors from the surrounding cytosol and can terminate signal propagation as a prelude to preparing receptors for destruction by the lysosomal compartment. In fact, stimulation by epidermal growth factor (EGF) increases the number and size of MVBs (White et al , 2006), whereas incapacitating the core MVB biogenesis machinery leads to excessive and prolonged signal propagation (Vaccari & Bilder, 2005). However, before becoming fully committed to ILV production, nascent MVBs sort transmembrane proteins and lipids within emanating tubules to other intracellular destinations, such as the trans ‐Golgi network, recycling endosomes, or back to the plasma membrane (Fig 1).Figure 1. Endocytic sorting structures and pathways. Schematic of the main types of sorting endosome and the trans ‐Golgi network. The arrows indicate the temporal relationship of the different sorting trajectories. ESCRTs, endosomal complexes required for transport; ILV, intralumenal vesicle; LBPA, lysobisphosphatidic acid; MVB, multovesicular body.At the recent EMBO Conference on Endocytic Machineries in Control of Cell Signalling and Tissue Morphogenesis, held in Chania, Crete and organized by Harald Stenmark and Gillian …