title: MVB-12, a fourth subunit of metazoan ESCRT-I, functions in receptor downregulation.
abstract: After ligand binding and endocytosis, cell surface receptors can continue to signal from endosomal compartments until sequestered from the cytoplasm. An important mechanism for receptor downregulation in vivo is via the inward budding of receptors into intralumenal vesicles to form specialized endosomes called multivesicular bodies (MVBs) that subsequently fuse with lysosomes, degrading their cargo. This process requires four heterooligomeric protein complexes collectively termed the ESCRT machinery. In yeast, ESCRT-I is a heterotetrameric complex comprised of three conserved subunits and a fourth subunit for which identifiable metazoan homologs were lacking. Using C. elegans, we identify MVB-12, a fourth metazoan ESCRT-I subunit. Depletion of MVB-12 slows the kinetics of receptor downregulation in vivo, but to a lesser extent than inhibition of other ESCRT-I subunits. Consistent with these findings, targeting of MVB-12 to membranes requires the other ESCRT-I subunits, but MVB-12 is not required to target the remaining ESCRT-I components. Both endogenous and recombinant ESCRT-I are stable complexes with a 1:1:1:1 subunit stoichiometry. MVB-12 has two human homologs that co-localize and co-immunoprecipitate with the ESCRT-I component TSG101. Thus, MVB-12 is a conserved core component of metazoan ESCRT-I that regulates its activity during MVB biogenesis.
authors: Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA. aaudhya@ucsd.edu
authors: Anjon
authors: A
authors: Audhya
authors: Ian X
authors: IX
authors: McLeod
authors: John R
authors: JR
authors: Yates
authors: Karen
authors: K
authors: Oegema
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D015536:Down-Regulation; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D015801:Helminth Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D033921:Vesicular Transport Proteins / Q000378:metabolism* / Q000502:physiology
chemical_list: D015801:Helminth Proteins; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D033921:Vesicular Transport Proteins