PMID- 37846480
OWN - NLM
STAT- MEDLINE
DCOM- 20231218
LR  - 20231218
IS  - 1469-3178 (Electronic)
IS  - 1469-221X (Print)
IS  - 1469-221X (Linking)
VI  - 24
IP  - 12
DP  - 2023 Dec 6
TI  - The HACE1 E3 ligase mediates RAC1-dependent control of mTOR signaling complexes.
PG  - e56815
LID - 10.15252/embr.202356815 [doi]
LID - e56815
AB  - 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.
CI  - (c) 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
FAU - Turgu, Busra
AU  - Turgu B
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada.
AD  - Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
FAU - El-Naggar, Amal
AU  - El-Naggar A
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada.
AD  - Department of Pathology and Laboratory Medicine, University of British Columbia, 
      Vancouver, BC, Canada.
AD  - Department of Pathology, Faculty of Medicine, Menoufia University, Shibin El Kom, 
      Egypt.
FAU - Kogler, Melanie
AU  - Kogler M
AUID- ORCID: 0000-0001-8107-2441
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, 
      Austria.
FAU - Tortola, Luigi
AU  - Tortola L
AUID- ORCID: 0000-0002-8480-2080
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, 
      Austria.
AD  - Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 
      Zurich, Switzerland.
FAU - Zhang, Hai-Feng
AU  - Zhang HF
AUID- ORCID: 0000-0001-8215-1870
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada.
FAU - Hassan, Mariam
AU  - Hassan M
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada.
FAU - Lizardo, Michael M
AU  - Lizardo MM
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada.
FAU - Kung, Sonia Hy
AU  - Kung SH
AUID- ORCID: 0000-0002-9230-8939
AD  - Department of Urological Sciences, Vancouver Prostate Centre, University of 
      British Columbia, Vancouver, BC, Canada.
FAU - Lam, Wan
AU  - Lam W
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada.
AD  - Department of Pathology and Laboratory Medicine, University of British Columbia, 
      Vancouver, BC, Canada.
FAU - Penninger, Josef M
AU  - Penninger JM
AUID- ORCID: 0000-0002-8194-3777
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, 
      Austria.
AD  - Department of Medical Genetics, Life Sciences Institute, University of British 
      Columbia, Vancouver, BC, Canada.
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
AD  - Helmholtz Centre for Infection Research, Braunschweig, Germany.
FAU - Sorensen, Poul H
AU  - Sorensen PH
AUID- ORCID: 0000-0001-7447-2199
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada.
AD  - Department of Pathology and Laboratory Medicine, University of British Columbia, 
      Vancouver, BC, Canada.
LA  - eng
GR  - PBEZP3_145993/SNSF_/Swiss National Science Foundation/Switzerland
PT  - Journal Article
DEP - 20231017
PL  - England
TA  - EMBO Rep
JT  - EMBO reports
JID - 100963049
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Ubiquitin)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - 0 (Rac1 protein, mouse)
RN  - EC 2.3.2.26 (HACE1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Ubiquitin/metabolism
MH  - *Ubiquitin-Protein Ligases/metabolism
PMC - PMC10702814
OTO - NOTNLM
OT  - E3 ubiquitin ligase
OT  - HACE1
OT  - RAC1
OT  - mTORC1 and mTORC2
OT  - tumor suppressor gene
COIS- Dr. Penninger is an EMBO member.
EDAT- 2023/10/17 06:42
MHDA- 2023/12/11 12:42
PMCR- 2023/10/17
CRDT- 2023/10/17 04:14
PHST- 2023/09/25 00:00 [revised]
PHST- 2023/01/11 00:00 [received]
PHST- 2023/09/29 00:00 [accepted]
PHST- 2023/12/11 12:42 [medline]
PHST- 2023/10/17 06:42 [pubmed]
PHST- 2023/10/17 04:14 [entrez]
PHST- 2023/10/17 00:00 [pmc-release]
AID - EMBR202356815 [pii]
AID - 10.15252/embr.202356815 [doi]
PST - ppublish
SO  - EMBO Rep. 2023 Dec 6;24(12):e56815. doi: 10.15252/embr.202356815. Epub 2023 Oct 
      17.