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1.
EMBO Rep ; 24(12): e56815, 2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-37846480

RESUMEN

HACE1 is a HECT family E3 ubiquitin-protein ligase with broad but incompletely understood tumor suppressor activity. Here, we report a previously unrecognized link between HACE1 and signaling complexes containing mammalian target of rapamycin (mTOR). HACE1 blocks mTORC1 and mTORC2 activities by reducing mTOR stability in an E3 ligase-dependent manner. Mechanistically, HACE1 binds to and ubiquitylates Ras-related C3 botulinum toxin substrate 1 (RAC1) when RAC1 is associated with mTOR complexes, including at focal adhesions, leading to proteasomal degradation of RAC1. This in turn decreases the stability of mTOR to reduce mTORC1 and mTORC2 activity. HACE1 deficient cells show enhanced mTORC1/2 activity, which is reversed by chemical or genetic RAC1 inactivation but not in cells expressing the HACE1-insensitive mutant, RAC1K147R . In vivo, Rac1 deletion reverses enhanced mTOR expression in KRasG12D -driven lung tumors of Hace1-/- mice. HACE1 co-localizes with mTOR and RAC1, resulting in RAC1-dependent loss of mTOR protein stability. Together, our data demonstrate that HACE1 destabilizes mTOR by targeting RAC1 within mTOR-associated complexes, revealing a unique ubiquitin-dependent process to control the activity of mTOR signaling complexes.


Asunto(s)
Ubiquitina-Proteína Ligasas , Animales , Ratones , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Serina-Treonina Quinasas TOR , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
2.
Pathogens ; 9(9)2020 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-32962019

RESUMEN

Despite routine implementation in urology, indwelling ureteral stents pose as a nidus for infection. Conditioning film accumulates on stents, which prime pathogen adhesion, promoting infectious biofilm formation. However, the extent to which conditioning film components play a role in facilitating bacterial adhesion and biofilm formation remains largely unknown. Here, we examined the interaction of previously identified stent-bound conditioning film components (fibrinogen, uromodulin, and albumin) with bacterial uropathogens. Cytoscopically removed stents were incubated with common uropathogens (Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus). Immunofluorescent double staining was performed to study the localization of uropathogens relative to stent-bound conditioning film proteins. Conditioning film components were identified on the external stent surface with some deposition in the inner lumen. Bacteria co-localized with fibrinogen, uromodulin, and albumin, suggesting a potential mechanism for stent-associated infections. Here, we determine strong co-localization between common uropathogenic bacterial species with prominent conditioning film components on ureteral stents. Further functional validation of interactions amongst these uropathogens and conditioning film proteins may enhance clinical management for stent-associated infections and development of improved stent technologies.

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