MORG1 limits mTORC1 signaling by inhibiting Rag GTPases.
Mol Cell
; 84(3): 552-569.e11, 2024 Feb 01.
Article
in En
| MEDLINE
| ID: mdl-38103557
ABSTRACT
Autophagy, an important quality control and recycling process vital for cellular homeostasis, is tightly regulated. The mTORC1 signaling pathway regulates autophagy under conditions of nutrient availability and scarcity. However, how mTORC1 activity is fine-tuned during nutrient availability to allow basal autophagy is unclear. Here, we report that the WD-domain repeat protein MORG1 facilitates basal constitutive autophagy by inhibiting mTORC1 signaling through Rag GTPases. Mechanistically, MORG1 interacts with active Rag GTPase complex inhibiting the Rag GTPase-mediated recruitment of mTORC1 to the lysosome. MORG1 depletion in HeLa cells increases mTORC1 activity and decreases autophagy. The autophagy receptor p62/SQSTM1 binds to MORG1, but MORG1 is not an autophagy substrate. However, p62/SQSTM1 binding to MORG1 upon re-addition of amino acids following amino acid's depletion precludes MORG1 from inhibiting the Rag GTPases, allowing mTORC1 activation. MORG1 depletion increases cell proliferation and migration. Low expression of MORG1 correlates with poor survival in several important cancers.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Monomeric GTP-Binding Proteins
/
GTP Phosphohydrolases
Limits:
Humans
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2024
Document type:
Article
Country of publication: