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

PloS One
Sung Tae KimYong Tae Kwon

Abstract

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 assoc...Continue Reading

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Citations

Jan 10, 2019·Proceedings of the National Academy of Sciences of the United States of America·Alexander Varshavsky
Jul 25, 2019·Proceedings of the National Academy of Sciences of the United States of America·Artem MelnykovAlexander Varshavsky
Dec 14, 2019·BMC Pediatrics· GunadiAkhmad Makhmudi
Jun 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Cheng DongJinrong Min
May 6, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jang-Hyun OhAlexander Varshavsky
Feb 27, 2021·Biochemical Society Transactions·Heather A Baker, Jonathan P Bernardini
Mar 16, 2021·Tumour Virus Research·Arushi VatsLawrence Banks
Jul 22, 2020·Biochemistry·Tri T M Vu, Alexander Varshavsky
Feb 24, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dominique LeboeufKonstantin I Piatkov

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Methods Mentioned

BETA
ubiquitination
transmission electron microscopy
protein assay
electrophoresis
affinity purification
scraping

Software Mentioned

Proteome
Adobe Photoshop
Adobe Illustrator
SEQUEST
PANTHER
SEQUEST®
Fiji
Ingenuity Pathway Analysis
SORCERER TM
Scaffold

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