TY - JOUR
T1 - Regulation of nucleo-cytosolic 26S proteasome translocation by aromatic amino acids via mTOR is essential for cell survival under stress
AU - Livneh, Ido
AU - Cohen-Kaplan, Victoria
AU - Fabre, Bertrand
AU - Abramovitch, Ifat
AU - Lulu, Chen
AU - Nataraj, Nishanth Belugali
AU - Lazar, Ikrame
AU - Ziv, Tamar
AU - Yarden, Yosef
AU - Zohar, Yaniv
AU - Gottlieb, Eyal
AU - Ciechanover, Aaron
N1 - Publisher Copyright:
© 2023
PY - 2023/9/21
Y1 - 2023/9/21
N2 - The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational modifications) have been unraveled, studying its adaptive compartmentalization in response to stress is just starting to emerge. We found that following amino acid starvation, the proteasome is translocated from its large nuclear pool to the cytoplasm—a response regulated by newly identified mTOR-agonistic amino acids—Tyr, Trp, and Phe (YWF). YWF relay their signal upstream of mTOR through Sestrin3 by disrupting its interaction with the GATOR2 complex. The triad activates mTOR toward its downstream substrates p62 and transcription factor EB (TFEB), affecting both proteasomal and autophagic activities. Proteasome translocation stimulates cytosolic proteolysis which replenishes amino acids, thus enabling cell survival. In contrast, nuclear sequestration of the proteasome following mTOR activation by YWF inhibits this proteolytic adaptive mechanism, leading to cell death, which establishes this newly identified pathway as a key stress-coping mechanism.
AB - The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational modifications) have been unraveled, studying its adaptive compartmentalization in response to stress is just starting to emerge. We found that following amino acid starvation, the proteasome is translocated from its large nuclear pool to the cytoplasm—a response regulated by newly identified mTOR-agonistic amino acids—Tyr, Trp, and Phe (YWF). YWF relay their signal upstream of mTOR through Sestrin3 by disrupting its interaction with the GATOR2 complex. The triad activates mTOR toward its downstream substrates p62 and transcription factor EB (TFEB), affecting both proteasomal and autophagic activities. Proteasome translocation stimulates cytosolic proteolysis which replenishes amino acids, thus enabling cell survival. In contrast, nuclear sequestration of the proteasome following mTOR activation by YWF inhibits this proteolytic adaptive mechanism, leading to cell death, which establishes this newly identified pathway as a key stress-coping mechanism.
KW - UPS
KW - aromatic amino acids
KW - mTOR
KW - proteasome dynamics
KW - protein quality control
KW - proteolysis
KW - stress response
UR - http://www.scopus.com/inward/record.url?scp=85171197441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85171197441&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2023.08.016
DO - 10.1016/j.molcel.2023.08.016
M3 - Article
C2 - 37738964
AN - SCOPUS:85171197441
SN - 1097-2765
VL - 83
SP - 3333-3346.e5
JO - Molecular cell
JF - Molecular cell
IS - 18
ER -