Universität zu Köln

Gollwitzer, Peter ORCID: 0000-0002-5145-6898, Gruetzmacher, Nina, Wilhelm, Sabine, Kuemmel, Daniel and Demetriades, Constantinos ORCID: 0000-0001-7813-7726 (2022). A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids. Nat. Cell Biol., 24 (9). S. 1394 - 1423. BERLIN: NATURE PORTFOLIO. ISSN 1476-4679

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Abstract

Amino acid availability controls mTORC1 activity via a heterodimeric Rag GTPase complex that functions as a scaffold at the lysosomal surface, bringing together mTORC1 with its activators and effectors. Mammalian cells express four Rag proteins (RagA-D) that form dimers composed of RagA/B bound to RagC/D. Traditionally, the Rag paralogue pairs (RagA/B and RagC/D) are referred to as functionally redundant, with the four dimer combinations used interchangeably in most studies. Here, by using genetically modified cell lines that express single Rag heterodimers, we uncover a Rag dimer code that determines how amino acids regulate mTORC1. First, RagC/D differentially define the substrate specificity downstream of mTORC1, with RagD promoting phosphorylation of its lysosomal substrates TFEB/TFE3, while both Rags are involved in the phosphorylation of non-lysosomal substrates such as S6K. Mechanistically, RagD recruits mTORC1 more potently to lysosomes through increased affinity to the anchoring LAMTOR complex. Furthermore, RagA/B specify the signalling response to amino acid removal, with RagB-expressing cells maintaining lysosomal and active mTORC1 even upon starvation. Overall, our findings reveal key qualitative differences between Rag paralogues in the regulation of mTORC1, and underscore Rag gene duplication and diversification as a potentially impactful event in mammalian evolution. Gollwitzer, Grutzmacher et al. and Figlia et al. establish that the various Rag GTPase genes and isoforms differentially regulate mTORC1 activity and distinctly modulate the responsiveness of mammalian cells to amino acid availability.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gollwitzer, Peter UNSPECIFIED orcid.org/0000-0002-5145-6898 UNSPECIFIED Gruetzmacher, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Wilhelm, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuemmel, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Demetriades, Constantinos UNSPECIFIED orcid.org/0000-0001-7813-7726 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-668640
DOI:	10.1038/s41556-022-00976-y
Journal or Publication Title:	Nat. Cell Biol.
Volume:	24
Number:	9
Page Range:	S. 1394 - 1423
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	1476-4679
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSFER-RNA SYNTHETASE; TRANSCRIPTION FACTOR; BINDING PROTEINS; GENE DUPLICATION; COMPLEX; RAGULATOR; TFEB; COLOCALIZATION; ARCHITECTURE; RECRUITMENT Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66864