Ring domains are essential for GATOR2-dependent mTORC1 activation

Cong Jiang; Xiaoming Dai; Shaohui He; Hongfei Zhou; Lan Fang; Jianping Guo; Songlei Liu; Tao Zhang; Weijuan Pan; Haihong Yu; Tianmin Fu; Dali Li; Hiroyuki Inuzuka; Ping Wang; Jianru Xiao; Wenyi Wei

doi:10.1016/j.molcel.2022.11.021

Ring domains are essential for GATOR2-dependent mTORC1 activation

Mol Cell. 2023 Jan 5;83(1):74-89.e9. doi: 10.1016/j.molcel.2022.11.021. Epub 2022 Dec 16.

Authors

Cong Jiang¹, Xiaoming Dai¹, Shaohui He², Hongfei Zhou², Lan Fang³, Jianping Guo¹, Songlei Liu⁴, Tao Zhang¹, Weijuan Pan⁵, Haihong Yu³, Tianmin Fu⁶, Dali Li⁵, Hiroyuki Inuzuka¹, Ping Wang³, Jianru Xiao⁷, Wenyi Wei⁸

Affiliations

¹ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
² 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.
³ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
⁴ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁵ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
⁶ Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, 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: [email protected].
⁸ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

Abstract

The GATOR2-GATOR1 signaling axis is essential for amino-acid-dependent mTORC1 activation. However, the molecular function of the GATOR2 complex remains unknown. Here, we report that disruption of the Ring domains of Mios, WDR24, or WDR59 completely impedes amino-acid-mediated mTORC1 activation. Mechanistically, via interacting with Ring domains of WDR59 and WDR24, the Ring domain of Mios acts as a hub to maintain GATOR2 integrity, disruption of which leads to self-ubiquitination of WDR24. Physiologically, leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. As such, WDR24 ablation or Ring deletion prevents mTORC1 activation, leading to severe growth defects and embryonic lethality at E10.5 in mice. Hence, our findings demonstrate that Ring domains are essential for GATOR2 to transmit amino acid availability to mTORC1 and further reveal the essentiality of nutrient sensing during embryonic development.

Keywords: Gator1; Gator2; NPRL2; Sestrin; WDR24; amino acid sensing; mTOR; ubiquitination.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Mechanistic Target of Rapamycin Complex 1 / genetics
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Multiprotein Complexes* / genetics
Multiprotein Complexes* / metabolism
Nuclear Proteins / metabolism
Signal Transduction
TOR Serine-Threonine Kinases* / genetics
TOR Serine-Threonine Kinases* / metabolism

Substances

Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Multiprotein Complexes
Nuclear Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding