title: UBE4B protein couples ubiquitination and sorting machineries to enable epidermal growth factor receptor (EGFR) degradation.
abstract: The signaling of plasma membrane proteins is tuned by internalization and sorting in the endocytic pathway prior to recycling or degradation in lysosomes. Ubiquitin modification allows recognition and association of cargo with endosomally associated protein complexes, enabling sorting of proteins to be degraded from those to be recycled. The mechanism that provides coordination between the cellular machineries that mediate ubiquitination and endosomal sorting is unknown. We report that the ubiquitin ligase UBE4B is recruited to endosomes in response to epidermal growth factor receptor (EGFR) activation by binding to Hrs, a key component of endosomal sorting complex required for transport (ESCRT) 0. We identify the EGFR as a substrate for UBE4B, establish UBE4B as a regulator of EGFR degradation, and describe a mechanism by which UBE4B regulates endosomal sorting, affecting cellular levels of the EGFR and its downstream signaling. We propose a model in which the coordinated action of UBE4B, ESCRT-0, and the deubiquitinating enzyme USP8 enable the endosomal sorting and lysosomal degradation of the EGFR.
authors.affiliation: From the Department of Neurobiology and Anatomy and the Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: Natalie
authors.initials: N
authors.lastname: Sirisaengtaksin
authors.forename: Monica
authors.initials: M
authors.lastname: Gireud
authors.forename: Qing
authors.initials: Q
authors.lastname: Yan
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kubota
authors.forename: Denisse
authors.initials: D
authors.lastname: Meza
authors.forename: Jack C
authors.initials: JC
authors.lastname: Waymire
authors.forename: Peter E
authors.initials: PE
authors.lastname: Zage
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bean
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology*; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D043743:Ubiquitin-Protein Ligase Complexes; C473697:UBE4B protein, human; D044767:Ubiquitin-Protein Ligases; C512478:EGFR protein, human; D066246:ErbB Receptors; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase
keywords: Deubiquitination; E3 Ubiquitin Ligase; ESCRT; Endocytosis; Endosomes; Protein Sorting; USP8; Ubiquitination