Gestational Leucylation Suppresses Embryonic T-Box Transcription Factor 5 Signal and Causes Congenital Heart Disease.
Adv Sci (Weinh)
; 9(15): e2201034, 2022 05.
Article
en En
| MEDLINE
| ID: mdl-35320615
ABSTRACT
Dysregulated maternal nutrition, such as vitamin deficiencies and excessive levels of glucose and fatty acids, increases the risk for congenital heart disease (CHD) in the offspring. However, the association between maternal amino-acid levels and CHD is unclear. Here, it is shown that increased leucine levels in maternal plasma during the first trimester are associated with elevated CHD risk in the offspring. High levels of maternal leucine increase embryonic lysine-leucylation (K-Leu), which is catalyzed by leucyl-tRNA synthetase (LARS). LARS preferentially binds to and catalyzes K-Leu modification of lysine 339 within T-box transcription factor TBX5, whereas SIRT3 removes K-Leu from TBX5. Reversible leucylation retains TBX5 in the cytoplasm and inhibits its transcriptional activity. Increasing embryonic K-Leu levels in high-leucine-diet fed or Sirt3 knockout mice causes CHD in the offspring. Targeting K-Leu using the leucine analogue leucinol can inhibit LARS activity, reverse TBX5 K-Leu modification, and decrease the occurrence of CHD in high-leucine-diet fed mice. This study reveals that increased maternal leucine levels increases CHD risk in the offspring through inhibition of embryonic TBX5 signaling, indicating that leucylation exerts teratogenic effects during heart development and may be an intervening target of CHD.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sirtuina 3
/
Cardiopatías Congénitas
Tipo de estudio:
Etiology_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Adv Sci (Weinh)
Año:
2022
Tipo del documento:
Article