Mitochondrial micropeptide MOXI promotes fibrotic gene transcription by translocation to the nucleus and bridging N-acetyltransferase 14 with transcription factor c-Jun.
Kidney Int
; 103(5): 886-902, 2023 05.
Article
en En
| MEDLINE
| ID: mdl-36804379
ABSTRACT
Progressive fibrosis is a hallmark of chronic kidney disease, but we lack effective treatments to halt this destructive process. Micropeptides (peptides of no more than 100 amino acids) encoded by small open reading frames represent a new class of eukaryotic regulators. Here, we describe that the micropeptide regulator of ß-oxidation (MOXI) regulates kidney fibrosis. MOXI expression was found to be up-regulated in human fibrotic kidney disease, and this correlated with the degree of fibrosis and loss of kidney function. MOXI was expressed in the cytoplasm and mitochondria of cultured tubular epithelial cells and translocated to the nucleus upon Transforming Growth Factor-ß1 stimulation. Deletion of Moxi protected mice against fibrosis and inflammation in the folic acid and unilateral ureteral obstruction models. As a potential molecular therapy, treatment with an antisense MOXI oligonucleotide effectively knocked-down MOXI expression and protected against kidney fibrosis in both models. Bimolecular fluorescence complementation identified the enzyme N-acetyltransferase 14 (Nat14) and transcription factor c-Jun as MOXI binding partners. The MOXI/Nat14/c-Jun complex enhances basal and Transforming Growth Factor-ß1 induced collagen I gene promoter activity. Phosphorylation at T49 is required for MOXI nuclear localization and for complex formation with Nat14 and c-Jun. Furthermore, mice with a MoxiT49A point mutation were protected in the models of kidney fibrosis. Thus, our studies demonstrate a key role for the micropeptide MOXI in kidney fibrosis and identify a new function of MOXI in forming a transcriptional complex with Nat14 and c-Jun.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Obstrucción Ureteral
/
Enfermedades Renales
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Kidney Int
Año:
2023
Tipo del documento:
Article
País de afiliación:
China