title: UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy.
abstract: The N-end rule pathway is a proteolytic system in which destabilizing N-terminal residues of short-lived proteins act as degradation determinants (N-degrons). Substrates carrying N-degrons are recognized by N-recognins that mediate ubiquitylation-dependent selective proteolysis through the proteasome. Our previous studies identified the mammalian N-recognin family consisting of UBR1/E3α, UBR2, UBR4/p600, and UBR5, which recognize destabilizing N-terminal residues through the UBR box. In the current study, we addressed the physiological function of a poorly characterized N-recognin, 570-kDa UBR4, in mammalian development. UBR4-deficient mice die during embryogenesis and exhibit pleiotropic abnormalities, including impaired vascular development in the yolk sac (YS). Vascular development in UBR4-deficient YS normally advances through vasculogenesis but is arrested during angiogenic remodeling of primary capillary plexus associated with accumulation of autophagic vacuoles. In the YS, UBR4 marks endoderm-derived, autophagy-enriched cells that coordinate differentiation of mesoderm-derived vascular cells and supply autophagy-generated amino acids during early embryogenesis. UBR4 of the YS endoderm is associated with a tissue-specific autophagic pathway that mediates bulk lysosomal proteolysis of endocytosed maternal proteins into amino acids. In cultured cells, UBR4 subpopulation is degraded by autophagy through its starvation-induced association with cellular cargoes destined to autophagic double membrane structures. UBR4 loss results in multiple misregulations in autophagic induction and flux, including synthesis and lipidation/activation of the ubiquitin-like protein LC3 and formation of autophagic double membrane structures. Our results suggest that UBR4 plays an important role in mammalian development, such as angiogenesis in the YS, in part through regulation of bulk degradation by lysosomal hydrolases.
authors: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Takafumi
authors: T
authors: Tasaki
authors: Sung Tae
authors: ST
authors: Kim
authors: Adriana
authors: A
authors: Zakrzewska
authors: Bo Eun
authors: BE
authors: Lee
authors: Min Jueng
authors: MJ
authors: Kang
authors: Young Dong
authors: YD
authors: Yoo
authors: Hyun Joo
authors: HJ
authors: Cha-Molstad
authors: Joonsung
authors: J
authors: Hwang
authors: Nak Kyun
authors: NK
authors: Soung
authors: Ki Sa
authors: KS
authors: Sung
authors: Su-Hyeon
authors: SH
authors: Kim
authors: Minh Dang
authors: MD
authors: Nguyen
authors: Ming
authors: M
authors: Sun
authors: Eugene C
authors: EC
authors: Yi
authors: Bo Yeon
authors: BY
authors: Kim
authors: Yong Tae
authors: YT
authors: Kwon
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D004707:Endoderm / Q000098:blood supply / Q000166:cytology / Q000201:enzymology; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008648:Mesoderm / Q000098:blood supply / Q000166:cytology / Q000201:enzymology; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics; D011247:Pregnancy; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015017:Yolk Sac / Q000098:blood supply* / Q000166:cytology / Q000196:embryology / Q000201:enzymology*
chemical_list: D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; C505833:UBR4 protein, human; D044767:Ubiquitin-Protein Ligases; C528904:Ubr4 protein, mouse