The HACE1 E3 ligase mediates RAC1-dependent control of mTOR signaling complexes.

Autor: Turgu B; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.; Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada., El-Naggar A; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.; Department of Pathology, Faculty of Medicine, Menoufia University, Shibin El Kom, Egypt., Kogler M; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Tortola L; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.; Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Zhang HF; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada., Hassan M; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada., Lizardo MM; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada., Kung SH; Department of Urological Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Lam W; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada., Penninger JM; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.; Helmholtz Centre for Infection Research, Braunschweig, Germany., Sorensen PH; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2023 Dec 06; Vol. 24 (12), pp. e56815. Date of Electronic Publication: 2023 Oct 17.
DOI: 10.15252/embr.202356815
Abstrakt: 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, RAC1 K147R . In vivo, Rac1 deletion reverses enhanced mTOR expression in KRas G12D -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.
(© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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