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

Takafumi Tasaki, Sung Tae Kim, Adriana Zakrzewska, Bo Eun Lee, Min Jueng Kang, Young Dong Yoo, Hyun Joo Cha-Molstad, Joonsung Hwang, Nak Kyun Soung, Ki Sa Sung, Su Hyeon Kim, Minh Dang Nguyen, Ming Sun, Eugene C. Yi, Bo Yeon Kim, Yongtae Kwon

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3800-3805
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number10
DOIs
StatePublished - 5 Mar 2013

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Yolk Sac
Autophagy
Blood Vessels
Endoderm
Proteolysis
Embryonic Development
Ubiquitins
Amino Acids
Membranes
Ubiquitination
Hydrolases
Mesoderm
Proteasome Endopeptidase Complex
Starvation
Endocytosis
Vacuoles
Cell Differentiation
Cultured Cells
Proteins
Mothers

Keywords

  • Cardiovascular system
  • Ubiquitin ligase

Cite this

Tasaki, Takafumi ; Kim, Sung Tae ; Zakrzewska, Adriana ; Lee, Bo Eun ; Kang, Min Jueng ; Yoo, Young Dong ; Cha-Molstad, Hyun Joo ; Hwang, Joonsung ; Soung, Nak Kyun ; Sung, Ki Sa ; Kim, Su Hyeon ; Nguyen, Minh Dang ; Sun, Ming ; Yi, Eugene C. ; Kim, Bo Yeon ; Kwon, Yongtae. / 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. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 10. pp. 3800-3805.
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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.",
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Tasaki, T, Kim, ST, Zakrzewska, A, Lee, BE, Kang, MJ, Yoo, YD, Cha-Molstad, HJ, Hwang, J, Soung, NK, Sung, KS, Kim, SH, Nguyen, MD, Sun, M, Yi, EC, Kim, BY & Kwon, Y 2013, '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', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 10, pp. 3800-3805. https://doi.org/10.1073/pnas.1217358110

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. / Tasaki, Takafumi; Kim, Sung Tae; Zakrzewska, Adriana; Lee, Bo Eun; Kang, Min Jueng; Yoo, Young Dong; Cha-Molstad, Hyun Joo; Hwang, Joonsung; Soung, Nak Kyun; Sung, Ki Sa; Kim, Su Hyeon; Nguyen, Minh Dang; Sun, Ming; Yi, Eugene C.; Kim, Bo Yeon; Kwon, Yongtae.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 10, 05.03.2013, p. 3800-3805.

Research output: Contribution to journalArticle

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T1 - 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

AU - Tasaki, Takafumi

AU - Kim, Sung Tae

AU - Zakrzewska, Adriana

AU - Lee, Bo Eun

AU - Kang, Min Jueng

AU - Yoo, Young Dong

AU - Cha-Molstad, Hyun Joo

AU - Hwang, Joonsung

AU - Soung, Nak Kyun

AU - Sung, Ki Sa

AU - Kim, Su Hyeon

AU - Nguyen, Minh Dang

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AU - Kim, Bo Yeon

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KW - Cardiovascular system

KW - Ubiquitin ligase

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