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Published on: July 21, 2018
PSAT1 inhibits mTORC1 activation by preventing Rag heterodimer formation in lung adenocarcinoma
Yuhan Liu1,2,3,4,5, Zhujun Cheng6, Jinjin Zhang7
1Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Abstract:
The mechanistic target of rapamycin complex 1 (mTORC1) integrates environmental cues, especially amino acids, to regulate metabolism and ultimately cancer progression. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in de novo serine synthesis and its overexpression has been reported to promote oncogenesis in various cancers. Knockdown of PSAT1 inhibits the proliferation and migration of cancer cells. However, our study found an interesting phenomenon that either PSAT1 overexpression or knockout promoted cell proliferation in lung adenocarcinoma (LUAD) which seemed to contradict traditional views. The mechanism was that PSAT1 preferentially bound to GTP-loaded RagB GTPases, preventing the formation of Rag heterodimers. This restricted the lysosome localization of mTORC1 and enhanced the basal level of macroautophagy/autophagy, which promoted the proliferative ability of LUAD cells. PSAT1 knockout resulted in Rag heterodimer formation and mTORC1 activation, promoting protein synthesis and cell proliferation. Additionally, PSAT1 knockout caused a compensatory upregulation of the serine transporter solute carrier family 1 member 5 (SLC1A5), increasing exogenous serine uptake. In conclusion, our study reveals a novel function of PSAT1 in regulation of mTORC1 that affects the proliferation of LUAD cells.Abbreviations: ATG5: autophagy-related 5; BECN1: Beclin 1; CQ: chloroquine; 4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GAP: GTPase-activating protein; GDP: Guanosine nucleotide diphosphate; GTP: Guanosine triphosphate; GTPase: guanosine triphosphatase; LAMP2: lysosome-associated membrane protein 2; LC3: microtubule-associated protein 1 light chain-3, LUAD: lung adenocarcinoma; mTORC1: mechanistic target of rapamycin complex 1; PCC: Pearson's correlation coefficient; PSAT1: Phosphoserine aminotransferase 1; Rag: Ras-related GTP binding; Raptor: regulatory-associated protein of mTOR; S6: ribosomal protein S6; S6K1: substrates S6 kinase 1; SLC1A5: solute carrier family 1 member 5; SSP: serine biosynthetic pathway; ULK1: unc-51 like autophagy activating kinase 1.
Insights
Phosphoserine aminotransferase 1 (PSAT1) impacts lung adenocarcinoma (LUAD) cell proliferation by regulating mTORC1 signaling. This study reveals PSAT1
Area of Science:
- Cell Biology
- Metabolic Regulation
- Cancer Research
Background:
- Mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient signals, particularly amino acids, to control cellular metabolism and cancer progression.
- Phosphoserine aminotransferase 1 (PSAT1), a key enzyme in serine synthesis, is often overexpressed in cancers, typically promoting oncogenesis.
- Previous research indicated PSAT1 knockdown inhibits cancer cell proliferation and migration, but its role in lung adenocarcinoma (LUAD) presented a complex scenario.
Purpose of the Study:
- To investigate the seemingly contradictory roles of PSAT1 in lung adenocarcinoma (LUAD) proliferation, where both overexpression and knockout promoted cell growth.
- To elucidate the underlying molecular mechanisms by which PSAT1 influences LUAD cell proliferation and mTORC1 signaling.
- To explore the interaction between PSAT1, Rag GTPases, and mTORC1 localization in the context of LUAD.
Main Methods:
- Investigated the interaction between PSAT1 and RagB GTPases using biochemical assays.
- Assessed the impact of PSAT1 modulation (overexpression and knockout) on mTORC1 localization to lysosomes.
- Quantified autophagy levels (macroautophagy/autophagy) and protein synthesis rates in response to PSAT1 alterations.
- Analyzed the expression of serine transporters, such as solute carrier family 1 member 5 (SLC1A5), following PSAT1 knockout.
Main Results:
- PSAT1 overexpression or knockout paradoxically promoted LUAD cell proliferation, contrary to established cancer biology.
- PSAT1 preferentially bound to GTP-loaded RagB, hindering Rag heterodimer formation and subsequently restricting mTORC1 lysosomal localization.
- This PSAT1-mediated inhibition of mTORC1 localization enhanced basal autophagy, promoting LUAD cell proliferation.
- PSAT1 knockout led to Rag heterodimer formation, mTORC1 activation, increased protein synthesis, and compensatory upregulation of the serine transporter SLC1A5.
Conclusions:
- This study uncovers a novel regulatory role for PSAT1 in controlling mTORC1 signaling pathways within LUAD cells.
- PSAT1's interaction with Rag GTPases modulates mTORC1 localization and autophagy, impacting LUAD cell proliferation.
- The findings challenge traditional views on PSAT1's function and highlight its complex involvement in LUAD pathogenesis.
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