PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2

doi:10.1016/j.cmet.2023.11.001

. 2023 Dec 5;35(12):2183-2199.e7.

doi: 10.1016/j.cmet.2023.11.001. Epub 2023 Nov 24.

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2

Cong Jiang¹, Jing Liu², Shaohui He³, Wei Xu³, Runzhi Huang⁴, Weijuan Pan⁵, Xiaolong Li⁶, Xiaoming Dai², Jianping Guo², Tao Zhang², Hiroyuki Inuzuka², Ping Wang⁴, John M Asara², Jianru Xiao⁷, Wenyi Wei⁸

Affiliations

¹ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Joint Research Center for Musculoskeletal Tumor of Shanghai Changzheng Hospital and University of Shanghai for Science and Technology, Spinal Tumor Center, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China; Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
² Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
³ Joint Research Center for Musculoskeletal Tumor of Shanghai Changzheng Hospital and University of Shanghai for Science and Technology, Spinal Tumor Center, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China.
⁴ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
⁵ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
⁶ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
⁷ Joint Research Center for Musculoskeletal Tumor of Shanghai Changzheng Hospital and University of Shanghai for Science and Technology, Spinal Tumor Center, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China. Electronic address: jianruxiao83@163.com.
⁸ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: wwei2@bidmc.harvard.edu.

PMID: 38006878
PMCID: PMC11192564 (available on 2024-12-05)
DOI: 10.1016/j.cmet.2023.11.001

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2

Cong Jiang et al. Cell Metab. 2023.

. 2023 Dec 5;35(12):2183-2199.e7.

doi: 10.1016/j.cmet.2023.11.001. Epub 2023 Nov 24.

Authors

Affiliations

¹ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Joint Research Center for Musculoskeletal Tumor of Shanghai Changzheng Hospital and University of Shanghai for Science and Technology, Spinal Tumor Center, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China; Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
² Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
³ Joint Research Center for Musculoskeletal Tumor of Shanghai Changzheng Hospital and University of Shanghai for Science and Technology, Spinal Tumor Center, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China.
⁴ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
⁵ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
⁶ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
⁷ Joint Research Center for Musculoskeletal Tumor of Shanghai Changzheng Hospital and University of Shanghai for Science and Technology, Spinal Tumor Center, Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China. Electronic address: jianruxiao83@163.com.
⁸ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: wwei2@bidmc.harvard.edu.

PMID: 38006878
PMCID: PMC11192564 (available on 2024-12-05)
DOI: 10.1016/j.cmet.2023.11.001

Abstract

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.

Keywords: GATOR1; NPRL2; PRMT1; arginine methylation; mTOR; methionine sensing; nutrient sensing.

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Conflict of interest statement

Declaration of interests W.W. is a co-founder and consultant for ReKindle Therapeutics.

References

1. Kim J, and Guan KL (2019). mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol 21, 63–71. 10.1038/s41556-018-0205-1. - DOI - PubMed
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[1] Kim J, and Guan KL (2019). mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol 21, 63–71. 10.1038/s41556-018-0205-1. - DOI - PubMed

[2] Kim J, and Guan KL (2019). mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol 21, 63–71. 10.1038/s41556-018-0205-1. - DOI - PubMed

[3] Liu GY, and Sabatini DM (2020). mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 21, 183–203. 10.1038/s41580-019-0199-y. - DOI - PMC - PubMed

[4] Liu GY, and Sabatini DM (2020). mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 21, 183–203. 10.1038/s41580-019-0199-y. - DOI - PMC - PubMed

[5] Ma XM, and Blenis J. (2009). Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10, 307–318. 10.1038/nrm2672. - DOI - PubMed

[6] Ma XM, and Blenis J. (2009). Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10, 307–318. 10.1038/nrm2672. - DOI - PubMed

[7] Saxton RA, and Sabatini DM (2017). mTOR Signaling in Growth, Metabolism, and Disease. Cell 169, 361–371. 10.1016/j.cell.2017.03.035. - DOI - PubMed

[8] Saxton RA, and Sabatini DM (2017). mTOR Signaling in Growth, Metabolism, and Disease. Cell 169, 361–371. 10.1016/j.cell.2017.03.035. - DOI - PubMed

[9] Mossmann D, Park S, and Hall MN (2018). mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer 18, 744–757. 10.1038/s41568-018-0074-8. - DOI - PubMed

[10] Mossmann D, Park S, and Hall MN (2018). mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer 18, 744–757. 10.1038/s41568-018-0074-8. - DOI - PubMed

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PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2

Affiliations

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2

Authors

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Abstract

Conflict of interest statement

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