The ubiquitin E3 ligase APC/CCdc20 mediates mitotic degradation of OGT.
J Biol Chem
; 300(7): 107448, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38844135
ABSTRACT
O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is the sole enzyme that catalyzes all O-GlcNAcylation reactions intracellularly. Previous investigations have found that OGT levels oscillate during the cell division process. Specifically, OGT abundance is downregulated during mitosis, but the underlying mechanism is lacking. Here we demonstrate that OGT is ubiquitinated by the ubiquitin E3 ligase, anaphase promoting complex/cyclosome (APC/C)-cell division cycle 20 (Cdc20). We show that APC/CCdc20 interacts with OGT through a conserved destruction box (D-box) Arg-351/Leu-354, the abrogation of which stabilizes OGT. As APC/CCdc20-substrate binding is often preceded by a priming ubiquitination event, we also used mass spectrometry and mapped OGT Lys-352 to be a ubiquitination site, which is a prerequisite for OGT association with APC/C subunits. Interestingly, in The Cancer Genome Atlas, R351C is a uterine carcinoma mutant, suggesting that mutations of the D-box are linked with tumorigenesis. Paradoxically, we found that both R351C and the D-box mutants (R351A/L354A) inhibit uterine carcinoma in mouse xenograft models, probably due to impaired cell division and proliferation. In sum, we propose a model where OGT Lys-352 ubiquitination primes its binding with APC/C, and then APC/CCdc20 partners with OGT through the D-box for its mitotic destruction. Our work not only highlights the key mechanism that regulates OGT during the cell cycle, but also reveals the mutual coordination between glycosylation and the cell division machinery.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
N-Acetilglucosaminiltransferasas
/
Ubiquitinación
/
Ciclosoma-Complejo Promotor de la Anafase
/
Mitosis
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2024
Tipo del documento:
Article
País de afiliación:
China