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PMID:16314518

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Citation

Kaneko-Oshikawa, C, Nakagawa, T, Yamada, M, Yoshikawa, H, Matsumoto, M, Yada, M, Hatakeyama, S, Nakayama, K and Nakayama, KI (2005) Mammalian E4 is required for cardiac development and maintenance of the nervous system. Mol. Cell. Biol. 25:10953-64

Abstract

Ubiquitin conjugation typically requires three classes of enzyme: E1, E2, and E3. A fourth type of enzyme (E4), however, was recently shown to be required for the degradation of certain types of substrate in yeast. We previously identified UFD2a (also known as E4B) as an E4 in mammals. UFD2a is exclusively expressed in cardiac muscle during mouse embryonic development, but it is abundant in neurons of adult mice and is implicated in the pathogenesis of neurodegenerative disease. The precise physiological function of this enzyme has remained largely unknown, however. Here, we show that mice lacking UFD2a die in utero, manifesting marked apoptosis in the developing heart. Polyubiquitylation activity for an E4 substrate was greatly reduced in Ufd2a(-/-) mouse embryonic fibroblasts. Furthermore, Ufd2a(+/-) mice displayed axonal dystrophy in the nucleus gracilis, as well as degeneration of Purkinje cells accompanied by endoplasmic reticulum stress. These animals also developed a neurological disorder. UFD2a thus appears to be essential for the development of cardiac muscle, as well as for the protection of spinocerebellar neurons from degeneration induced by endoplasmic reticulum stress.

Links

PubMed PMC1316961 Online version:10.1128/MCB.25.24.10953-10964.2005

Keywords

Animals; Axons/pathology; Embryo, Mammalian/chemistry; Embryo, Mammalian/cytology; Endoplasmic Reticulum/metabolism; Gene Expression Regulation, Developmental; Heart/embryology; Mice; Mice, Neurologic Mutants; Myocardium/cytology; Nervous System; Neuroaxonal Dystrophies/genetics; Organogenesis/genetics; Polyubiquitin/metabolism; Purkinje Cells/pathology; Ubiquitin-Protein Ligases/deficiency; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:UBE4B

acts_upstream_of_or_within

GO:0000209: protein polyubiquitination

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3611069

P

Seeded From UniProt

complete

MOUSE:UBE4B

acts_upstream_of_or_within

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3611069

P

  • occurs_in:(CL:0000117)

Seeded From UniProt

complete

MOUSE:UBE4B

acts_upstream_of_or_within

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3611069

P

  • occurs_in:(CL:0000121)
  • occurs_in:(EMAPA:35211)

Seeded From UniProt

complete

MOUSE:UBE4B

acts_upstream_of_or_within

GO:0003222: ventricular trabecula myocardium morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3611069

P

Seeded From UniProt

complete

MOUSE:UBE4B

acts_upstream_of_or_within

GO:0044257: cellular protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3611069

P

Seeded From UniProt

complete

MOUSE:UBE4B

acts_upstream_of_or_within

GO:0034976: response to endoplasmic reticulum stress

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3611069

P

  • occurs_in:(CL:0000117)
  • occurs_in:(EMAPA:16894)

Seeded From UniProt

complete


See also

References

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