Detailed Nature Paper: Discovery of a new leucine receptor protein SAR1B that regulates lung cancer through mTORC1

The full name of mTOR is the mammalian target of rapamycin ( mTOR ), which plays an important role in cell life activity and metabolic regulation.

The full name of mTOR is the mammalian target of rapamycin ( mTOR ), which plays an important role in cell life activity and metabolic regulation.

The process of

2021 Nian 7 Yue 21 days, the future Institute of Technology School of Molecular Medicine, Peking University, Beijing University - Tsinghua University Joint Center for Life Sciences, Beijing future genetic diagnosis -tech innovation center Liu Ying research group at diagnosisNaturepublished online entitled: Sar1b Senses Leucine A research paper on levels to regulate mTORC1 signalling.

The study reported a novel leucine receptor protein SAR1B 's regulatory mechanism on mTORC1 , and found that SAR1B-mTORC1 signaling plays a potential role in human non-small cell lung cancer

The study reported a novel leucine receptor protein SAR1B 's regulatory mechanism on mTORC1 , and found that SAR1B-mTORC1 signaling plays a potential role in human non-small cell lung cancer

Research ideas and results display Research ideas and results display

SAR1B controls leucine-dependent mTORC1 signaling

SAR1B controls the leucine-dependent mTORC1 signal SAR1B controls the leucine-dependent mTORC1 signal

Researchers have attempted to find more amino acid signal to pass to mTORC1 upstream regulatory factor, and found to participate in a vesicle formed G protease --SAR1B may be in the absence of an amino acid GATOR2 binding knockdown SAR1B cause mTORC1 to lack amino acid insensitive Thus, the activity continues to be maintained, and the lack of SAR1B specifically affects the regulation of leucine on mTORC1 , but has no effect on other amino acids, indicating that SAR1B may be a leucine receptor

Researchers have attempted to find more amino acid signal to pass to mTORC1 upstream regulatory factor, and found to participate in a vesicle formed G protease --SAR1B may be in the absence of an amino acid GATOR2 binding knockdown SAR1B cause mTORC1 to lack amino acid insensitive Thus, the activity continues to be maintained, and the lack of SAR1B specifically affects the regulation of leucine on mTORC1 , but has no effect on other amino acids, indicating that SAR1B may be a leucine receptor

Through immunoprecipitation and in vitro experiments to study the interaction between proteins and their components, the researchers concluded that when leucine is lacking, SAR1B binds to and inhibits the mTORC1 activator GATOR2 complex, inactivating mTORC1 and synthesizing Metabolism stagnates; when leucine is sufficient, SAR1B binds to leucine, undergoes a conformational change, dissociates from GATOR2 , activates mTORC1 , and initiates anabolic metabolism

Figure 1 : SAR1B senses the level of leucine in cells and regulates mTORC1 signal through GATOR2

Figure 1 : SAR1B senses the level of leucine in cells and regulates mTORC1 signal through GATOR2

SAR1B and Sestrin2 are different in the perception of leucine

SAR1B and Sestrin2 have differences in the perception of leucine SAR1B and Sestrin2 have differences in the perception of leucine

The above experiments indicate that SAR1B and Sestrin2 may act as leucine receptors at the same time , but the two have different modes of action.

The above experiments indicate that SAR1B and Sestrin2 may act as leucine receptors at the same time , but the two have different modes of action.

1 ) They bind to different subunits of GATOR2 .

2 ) Their binding affinity to leucine is different.

3 ) They recognize different structural features of leucine

4 ) The two receptor proteins have differences in tissue distribution, and in muscle, the two receptors coordinately regulate mTORC1 ( 2c )

Figure 2 : The difference between SAR1B and Sestrin2 and the synergistic regulation of mTORC1 signal pattern between the two

Figure 2 : The difference between SAR1B and Sestrin2 and the synergistic regulation of mTORC1 signal pattern between the two

SAR1B exerts a potential inhibitory effect in human non-small cell lung cancer

SAR1B exerts a potential inhibitory effect in human non-small cell lung cancer SAR1B exerts a potential inhibitory effect in human non-small cell lung cancer

Human lung squamous cell carcinoma and adenocarcinoma Sar1b statistics of the number of mutations and mutation frequency display, Sar1b in human lung squamous cell carcinoma and adenocarcinoma are often missing, Further, while two human lung fibroblasts silencing SAR1B and its homologous protein SAR1A in cells ( IMR-90 and HFL1 ) eliminate leucine sensitivity and structurally activate mTORC1 .

Human lung squamous cell carcinoma and adenocarcinoma Sar1b statistics of the number of mutations and mutation frequency display, Sar1b in human lung squamous cell carcinoma and adenocarcinoma are often missing, Further, while two human lung fibroblasts silencing SAR1B and its homologous protein SAR1A in cells ( IMR-90 and HFL1 ) eliminate leucine sensitivity and structurally activate mTORC1 .

Therefore, the researchers proposed that the SAR1B-mTORC1 signal may play a potential role in human non-small cell lung cancer, and subsequently established a subcutaneous xenograft tumor model ( 3a ) and an orthotopic xenograft tumor model (3c) to prove this hypothesis
.
The study found that the lack of SAR1A and SAR1B promotes the growth of subcutaneous tumors ( 3b ), and at the same time promotes the growth of tumors in the lungs of mice ( 3d ).
In addition, representative immunohistochemical images show that the lack of SAR1A and SAR1B can promote metabolic reprogramming in tumors ( 3e).
) To promote the growth and proliferation of tumors
.
The above experimental results indicate that SAR1B may play a potential inhibitory effect in human non-small cell lung cancer
.

Therefore, the researchers proposed that the SAR1B-mTORC1 signal may play a potential role in human non-small cell lung cancer, and subsequently established a subcutaneous xenograft tumor model ( 3a ) and an orthotopic xenograft tumor model (3c) to prove this hypothesis
.
The study found that the lack of SAR1A and SAR1B promotes the growth of subcutaneous tumors ( 3b ), and at the same time promotes the growth of tumors in the lungs of mice ( 3d ).
In addition, representative immunohistochemical images show that the lack of SAR1A and SAR1B can promote metabolic reprogramming in tumors ( 3e).
) To promote the growth and proliferation of tumors
.
The above experimental results indicate that SAR1B may play a potential inhibitory effect in human non-small cell lung cancer
.

Figure 3 : SAR1B is a potential tumor suppressor in lung cancer

Figure 3 : SAR1B is a potential tumor suppressor in lung cancer

In summary, this study discovered a new leucine receptor protein SAR1B , and analyzed its molecular mechanism that senses leucine and regulates mTORC1 signaling through GATOR2 .
Through bioinformatics analysis and establishment of a nude mouse orthotopic tumor model, the researchers proved that SAR1B is a potential tumor suppressor factor for human non-small cell lung cancer, and it is promising to become a new type of biomarker for non-small cell lung cancer.
Therapies provide new drug targets .

In summary, this study discovered a new leucine receptor protein SAR1B , and analyzed its molecular mechanism that senses leucine and regulates mTORC1 signaling through GATOR2 .
Through bioinformatics analysis and establishment of a nude mouse orthotopic tumor model, the researchers proved that SAR1B is a potential tumor suppressor factor for human non-small cell lung cancer, and it is promising to become a new type of biomarker for non-small cell lung cancer.
Therapies provide new drug targets .

references:

references:

1.
Robert A.
Saxton, David M.
Sabatini.
.
mTOR Signaling in Growth, Metabolism, and Disease.
Cell 168, 960-976 (2017)

1.
Robert A.
Saxton, David M.
Sabatini.
.
mTOR Signaling in Growth, Metabolism, and Disease.
Cell 168, 960-976 (2017)

2.
Bar-Peled, L.
et al.
A Tumor suppressor complex with GAP activity for the Rag GTPasesthat signal amino acid sufficiency to mTORC1.
Science 340, 1100–1106 (2013)

2.
Bar-Peled, L.
et al.
A Tumor suppressor complex with GAP activity for the Rag GTPasesthat signal amino acid sufficiency to mTORC1.
Science 340, 1100–1106 (2013)

3.
Wolfson, RL et al.
Sestrin2 is a leucine sensor for the mTORC1 pathway.
Science 351,43–48 (2016)

3.
Wolfson, RL et al.
Sestrin2 is a leucine sensor for the mTORC1 pathway.
Science 351,43–48 (2016)

4.
Zanetti, G.
, Pahuja, KB, Studer, S.
, Shim, S.
& Schekman, R: COPII and the regulation of protein sorting in mammals.
Nat.
Cell Biol.
14, 20–28 (2012)

4.
Zanetti, G.
, Pahuja, KB, Studer, S.
, Shim, S.
& Schekman, R: COPII and the regulation of protein sorting in mammals.
Nat.
Cell Biol.
14, 20–28 (2012)

in This message