The N-recognin UBR4 of the N-end rule pathway is required for neurogenesis and homeostasis of cell surface proteins

The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of proteins act as a class of degrons (N-degrons) that determine the half-lives of proteins. We have previously identified a family of mammals N-recognins (termed UBR1, UBR2, UBR4/p600, and UBR5/EDD) whose conserve...

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Bibliographic Details
Published in:PloS one 2018-08, Vol.13 (8), p.e0202260-e0202260
Main Authors: Kim, Sung Tae, Lee, Yoon Jee, Tasaki, Takafumi, Hwang, Joonsung, Kang, Min Jueng, Yi, Eugene C, Kim, Bo Yeon, Kwon, Yong Tae
Format: Article
Language:English
Subjects:
Abnormalities
Adhesion
Amino acids
Analysis
Analytical chemistry
Animals
Autophagosomes - metabolism
Autophagy
Biology and Life Sciences
Calmodulin-Binding Proteins - genetics
Calmodulin-Binding Proteins - metabolism
Cancer
Cell adhesion
Cell adhesion & migration
Cell Adhesion - physiology
Cell Line, Tumor
Cell Membrane - metabolism
Cell surface
Cellular signal transduction
Cytoskeletal Proteins - genetics
Cytoskeletal Proteins - metabolism
Embryos
Endocytosis - physiology
Fibroblasts - metabolism
Genomes
Growth factors
HEK293 Cells
HeLa Cells
Homeostasis
Homeostasis - physiology
Humans
Integrity
Lysosomes
Lysosomes - metabolism
Medical research
Medicine
Medicine and Health Sciences
Metabolism
Mice
Mice, Knockout
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Multivesicular Bodies - metabolism
Neurogenesis
Neurogenesis - physiology
Phagosomes
Pharmacy
Phenotypes
Proteasomes
Protein folding
Proteins
Proteolysis
Proteome
Proteomes
Proteomics
Regulation
Research and Analysis Methods
Substrates
Ubiquitin
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary:The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of proteins act as a class of degrons (N-degrons) that determine the half-lives of proteins. We have previously identified a family of mammals N-recognins (termed UBR1, UBR2, UBR4/p600, and UBR5/EDD) whose conserved UBR boxes bind N-degrons to facilitate substrate ubiquitination and proteasomal degradation via the ubiquitin-proteasome system (UPS). Amongst these N-recognins, UBR1 and UBR2 mediate ubiquitination and proteolysis of short-lived regulators and misfolded proteins. Here, we characterized the null phenotypes of UBR4-deficient mice in which the UBR box of UBR4 was deleted. We show that the mutant mice die around embryonic days 9.5-10.5 (E9.5-E10.5) associated with abnormalities in various developmental processes such as neurogenesis and cardiovascular development. These developmental defects are significantly attributed to the inability to maintain cell integrity and adhesion, which significantly correlates to the severity of null phenotypes. UBR4-loss induces the depletion of many, but not all, proteins from the plasma membrane, suggesting that UBR4 is involved in proteome-wide turnover of cell surface proteins. Indeed, UBR4 is associated with and required to generate the multivesicular body (MVB) which transiently store endocytosed cell surface proteins before their targeting to autophagosomes and subsequently lysosomes. Our results suggest that the N-recognin UBR4 plays a role in the homeostasis of cell surface proteins and, thus, cell adhesion and integrity.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0202260