BBB Seminar - Jean Gruenberg
Multivesicular endosome biogenesis and signaling
Department of Biochemistry, University of Geneva, Switzerland
During endocytic membrane transport, cell surface molecules destined for late endosomes and lysosomes, e.g. epidermal growth factor (EGF) receptor and other down-regulated signaling receptors, are sequentially incorporated into membrane invaginations with opposite topology. After internalization via clathrin-coated vesicles, which bud into the cytoplasm, and delivery to early endosomes, activated and ubiquitinylated receptors are sorted into intralumenal vesicles that form within multivesicular regions of the early endosome. In these intralumenal vesicles, the cytoplasmic domains of receptor molecules are disconnected from the signaling response, being no longer accessible to downstream signaling effectors. The multivesicular endosomal regions acidify and detach - or mature - from early endosomes, giving rise to an acidic multivesicular endosome (or multivesicular body, MVB). Eventually, lumenal vesicles and their protein cargo are delivered to late endosomes and lysosomes for degradation. However, some proteins and lipids present in intralumenal vesicles are not targeted for degradation in lysosomes. These molecules are presumably recycled, e.g. to the Golgi or the plasma membrane, via backfusion of intralumenal vesicles with the endosome limiting membrane - a process apparently hijacked by some pathogenic agents. The fate of the endocytosed EGF receptor during transport in acidic endosomes will be discussed, as well as the EGF transcriptional response when interfering with sorting into intralumenal vesicles.
Host: Hans-Hermann Gerdes, Department of Biomedicine