On November 24th, the team led by Professor Xiao Jianru from Orthopedics Biomedicine and Instrument Innovation Research Institute and the team led by Professor Wei Wenyi from Harvard Medical University together published a research paper in International famous medical journal Cell Metabolism titled “PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2”. Jiang Cong, who is a postgraduate jointly cultivated by Harvard Medical University was the first author. Professor Xiao Jianru and Professor Wei Wenyi were both the corresponding authors. Liu Jing from Harvard Medical University, He Shaohui and Xu Wei from Shanghai Changzheng Hospital Orthopedics were both the first authors. USST and Shanghai Changzheng Hospital Joint Research Center was the first unit.
Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.
mTORC1 (mechanistic target of rapamycin complex 1) is a master regulator of cell growth and homeostasis in response to diverse environmental cues, including amino acids.1,2 Dysregulation of mTORC1 signaling has been implicated in a variety of human diseases, including cancer, diabetes, and neurological disorders.3,4,5 The amino acid signal is sequentially transmitted to mTORC1 through Rag GTPase-mediated (GTP, guanosine triphosphate) lysosomal translocation and Rheb-mediated activation of the mTORC1 complex.6,7,8,9 Several protein complexes have been identified to govern the amino acid sensing and subsequent activation of mTORC1 via regulating the activation status of Rag GTPases.10,11,12,13,14,15 Among these, GATOR1 (GAP activity toward Rags 1) and FLCN (folliculin)-FNIP (folliculin interacting protein) have been identified to function as GTPase-activating proteins (GAPs) for RagA/B and RagC/D, respectively, and are frequently mutated in many human diseases.13,16,17,18,19 Of note, GATOR1 consists of NPRL2 (NPR2 like), NPRL3 (NPR3 like), and DEPDC5 (DEP domain containing 5), of which NPRL2 catalyzes GATOR1-stimulated GTP hydrolysis via inserting its arginine finger into the nucleotide-binding pocket of RagA/B GTPase.20,21 Furthermore, there are alternative pathways to activate mTORC1 that are independent of Rag proteins.22 For instance, in the context of glutamine-induced mTORC1 activation, Arf1 can serve as a substitute for Rag.23 Additionally, amino acids facilitate the loading of GTP onto Rab1a, subsequently initiating an interaction between Rheb and mTORC1 in the Golgi.24
GATOR2 transmits leucine and arginine availabilities to mTORC1 via directly interacting with the respective sensor proteins, such as Sestrin2, SARB1 (secretion associated Ras related GTPase 1B), and Castor1, and antagonizes the function of GATOR1.25,26,27 On the other hand, methionine sensing by mTORC1 adopts a distinct mechanism via impinging on GATOR1 instead of GATOR2.28 Under the conditions of methionine scarcity, intracellular SAM (S-adenosyl methionine) is dramatically reduced to a level below its dissociation constant (Kd) with SAMTOR (S-adenosylmethionine sensor upstream of mTORC1), and the non-SAM-loaded SAMTOR binds to GATOR1 and inhibits mTORC1 signaling.28 However, SAMTOR’s enzymatic activity is dispensable for its role in inactivating mTORC1 signaling,28 suggesting that additional sensing mechanisms exist in parallel with SAMTOR to suppress the GAP activity of GATOR1 under methionine-sufficient conditions (Figure S1A).
Here, they report that PRMT1 (protein arginine methyltransferase 1) is essential for methionine-mediated mTORC1 activation via directly sensing the intracellular levels of SAM. Under methionine-sufficient conditions, elevated cytosolic SAM disassociates SAMTOR from GATOR1, which confers GATOR1 interaction with PRMT1 to methylate NPRL2 and suppress the GAP activity of GATOR1, leading to mTORC1 activation. More importantly, the hepatic Prmt1-Nprl2-mTORC1 axis plays a key role in orchestrating the organismal response to dietary methionine restriction in aged mice, establishing PRMT1 as a physiological SAM sensor of mTORC1 signaling.
In conclusion, their study reveals a novel function of PRMT1 in methionine sensing by mTORC1 signaling via utilizing SAM as a cofactor to methylate NPRL2 and antagonize the GAP activity of GATOR1, establishing PRMT1 as a conserved physiological methionine/SAM sensor of mTORC1 signaling to dictate hepatic insulin sensitivity.
