Universität zu Köln

Acharya, Aishwarya Atul ORCID: 0000-0003-4237-4839 (2026). Molecular principles of mTORC1 localization and signaling. PhD thesis, Universität zu Köln.

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Abstract

Nutrient sensing is essential for proper cellular function — to ensure that supply meets demand and to adjust the metabolic program from anabolism to catabolism if resources are scarce. The mammalian/mechanistic target of Rapamycin complex 1 (mTORC1) is a growth-promoting signaling complex that is critical for sensing nutrient availability and regulating cellular processes accordingly. Information about nutrient availability is conveyed from a complex upstream regulatory network to mTORC1 via two small GTPases — Rags and Rheb, which primarily influence mTORC1 lysosomal localization and activity, respectively. A large amount of research effort investigating the intricate mechanisms by which mTORC1 is recruited to the lysosomal membrane has culminated in a model which proposes that the nucleotide-binding state of the Rag GTPases is responsive to nutrient sufficiency, such that mTORC1 is recruited to lysosomes by Rags in their active configuration and delocalized away from lysosomes when Rags are in their inactive configuration due to nutrient insufficiency. However, how mTORC1 is released from lysosomes under basal conditions, conceivably an imperative for sustaining the activity of mTORC1 toward its non-lysosomal substrates, remains elusive. Here, I show that mTORC1 regulates its own lysosomal localization in an activity-dependent manner by impacting the GATOR1-RagA axis. Specifically, inactive mTORC1 triggers locking of the Rags in their active conformation, impairing release from lysosomes unless prior activation has taken place. This reveals that mTORC1 itself triggers a molecular fail-safe mechanism to prevent the release of non-activated complexes, thus preventing its futile cycling, and suggests that mTORC1 activity and localization bilaterally regulate each other. A key input to mTORC1 is its direct activator Rheb, which lies downstream of the Tuberous Sclerosis Complex (TSC), a potent inhibitor of the pathway. Past work has indicated that in TSC loss-of-function models, not only mTORC1 activity but also its localization is affected, but the underlying molecular cause was not fully decoded. Here, I demonstrate that hyperactive Rheb drives the forced lysosomal localization of mTORC1 by functioning as a secondary anchor on the lysosomal landscape. In sum, this work unravels two important facets of mTORC1 regulation that affect its localization and signaling.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Acharya, Aishwarya Atul aacharya@age.mpg.de https://orcid.org/0000-0003-4237-4839 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-800699
Date:	2026
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language mTORC1, Rag GTPases, Rheb, TFEB, lysosomes, nutrient sensing, signaling English
Date of oral exam:	17 March 2025
Referee:	Name Academic Title Demetriades, Constantinos Dr. Riemer, Jan Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80069