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Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway

ML. Valenstein, PV. Lalgudi, X. Gu, JF. Kedir, MS. Taylor, RR. Chivukula, DM. Sabatini

. 2024 ; 121 (35) : e2322755121. [pub] 20240820

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019260

Grantová podpora
N/A Lustgarten Foundation (The Lustgarten Foundation)
TS200035 U.S. Department of Defense (DOD)
CA103866 HHS | NIH (NIH)
T32 GM007753 NIGMS NIH HHS - United States
F30 CA236179 NCI NIH HHS - United States
N/A LEO Fondet (LEO Foundation)
W81XWH-21-1-0260 U.S. Department of Defense (DOD)
R01 CA129105 NCI NIH HHS - United States
AI47389 HHS | NIH (NIH)
N/A CAS | Ústav organické chemie a biochemie Akademie věd České republiky (IOCB, CAS)
R01 AI047389 NIAID NIH HHS - United States
R01 CA103866 NCI NIH HHS - United States
CA129105 HHS | NIH (NIH)
N/A Massachusetts General Hospital (MGH)
F30 CA228229 NCI NIH HHS - United States
N/A Burroughs Wellcome Fund (BWF)
R37 AI047389 NIAID NIH HHS - United States
N/A Pershing Square Foundation (PSF)
N/A Massachusetts Institute of Technology (MIT)
N/A Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (KI)

E-zdroje Online Plný text

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Open Access Digital Library od 1915-01-15

Odkazy

PubMed 39163330
DOI 10.1073/pnas.2322755121
Knihovny.cz E-zdroje

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the "GATOR" supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag-Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.

Citace poskytuje Crossref.org

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