DataVXAdvanced SciencePaper
journal article·2024-03Open access

TRAF4‐Mediated LAMTOR1 Ubiquitination Promotes mTORC1 Activation and Inhibits the Inflammation‐Induced Colorectal Cancer Progression

Linlin Zhao, Ni Gao, Xiaoping Peng, Lei Chen, Tong Meng, Cong Jiang, Jiali Jin, Jiawen Zhang, Qiuhui Duan, Hongling Tian, Linjun Weng, Xinbo Wang, Xiao Tan, Yaxu Li, Huanlong Qin, Jian Yuan, Xin Ge, Lu Deng, Ping Wang

Advanced Science· Volume 11· Issue 12
Publisher pageOpen full text
Source abstract

Abstract

Abstract Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase that integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activation requires tethering to lysosomes by the Ragulator‐Rag complex. However, the dynamic regulation of the interaction between Ragulator and Rag guanosine triphosphatase (GTPase) remains unclear. In this study, that LAMTOR1, an essential component of Ragulator, is dynamically ubiquitinated depending on amino acid abundance is reported. It is found that the E3 ligase TRAF4 directly interacts with LAMTOR1 and catalyzes the K63‐linked polyubiquitination of LAMTOR1 at K151. Ubiquitination of LAMTOR1 by TRAF4 promoted its binding to Rag GTPases and enhanced mTORC1 activation, K151R knock‐in or TRAF4 knock‐out blocks amino acid‐induced mTORC1 activation and accelerates the development of inflammation‐induced colon cancer. This study revealed that TRAF4‐mediated LAMTOR1 ubiquitination is a regulatory mechanism for mTORC1 activation and provides a therapeutic target for diseases involving mTORC1 dysregulation.
Source: crossref · Quality: baseline

Research context

Catalysis & surfaces

OpenAlex topics: PI3K/AKT/mTOR signaling in cancer · Ubiquitin and proteasome pathways · Cancer-related Molecular Pathways

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Tongji University Cancer Center Shanghai Tenth People's Hospital Shanghai Frontiers Science Center of Nanocatalytic Medicine School of Medicine Tongji University Shanghai 200092 P. R. China

Department of Orthopedics Shanghai General Hospital School of Medicine Shanghai Jiaotong University Shanghai 200940 P. R. China

Department of Gastrointestinal Surgery Shanghai Tenth People's Hospital Tongji University Shanghai 200092 P. R. China

Research Institute of Intestinal Diseases Tongji University School of Medicine Shanghai 200092 P. R. China

Department of Biochemistry and Molecular Biology Tongji University School of Medicine Shanghai 200092 P. R. China

Research Center for Translational Medicine Shanghai East Hospital Tongji University School of Medicine Shanghai 200120 P. R. China

College of Animal Science and Technology Northwest A&F University Yangling Shaanxi 712100 P. R. China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Fundamental Research Funds for the Central Universities · Postdoctoral Research Foundation of China · Shanghai Rising-Star Program

References (49)

Show source-provided references
1. 10.1038/s41580-023-00670-310.1038/s41580-023-00670-3 ↗
2. 10.1152/physrev.00026.202010.1152/physrev.00026.2020 ↗
3. 10.1016/j.cell.2022.04.01310.1016/j.cell.2022.04.013 ↗
4. 10.1038/s41580-019-0199-y10.1038/s41580-019-0199-y ↗
5. 10.1126/science.115753510.1126/science.1157535 ↗
6. 10.1101/gad.111000310.1101/gad.1110003 ↗
7. 10.1016/j.cell.2010.02.02410.1016/j.cell.2010.02.024 ↗
8. 10.1126/science.123204410.1126/science.1232044 ↗
9. 10.1126/scisignal.200411210.1126/scisignal.2004112 ↗
10. 10.1038/nature2502310.1038/nature25023 ↗
11. 10.1073/pnas.181172711510.1073/pnas.1811727115 ↗
12. 10.1016/j.cell.2012.07.03210.1016/j.cell.2012.07.032 ↗
13. 10.1126/science.aao158310.1126/science.aao1583 ↗
14. 10.1016/j.molcel.2017.10.01610.1016/j.molcel.2017.10.016 ↗
15. 10.1038/s41467-017-01762-310.1038/s41467-017-01762-3 ↗
16. 10.1016/j.canlet.2022.01.00110.1016/j.canlet.2022.01.001 ↗
17. 10.3389/fncel.2019.0011510.3389/fncel.2019.00115 ↗
18. 10.1038/s41556-018-0148-610.1038/s41556-018-0148-6 ↗
19. 10.1146/annurev.biochem.67.1.42510.1146/annurev.biochem.67.1.425 ↗
20. 10.1016/j.molcel.2013.06.02010.1016/j.molcel.2013.06.020 ↗
21. 10.1038/nature2234410.1038/nature22344 ↗
22. 10.1016/j.molcel.2011.08.02910.1016/j.molcel.2011.08.029 ↗
23. 10.1074/jbc.M117.80953310.1074/jbc.M117.809533 ↗
24. 10.1016/j.molcel.2015.03.03310.1016/j.molcel.2015.03.033 ↗
25. 10.1016/j.molcel.2015.05.01010.1016/j.molcel.2015.05.010 ↗
26. 10.1038/s41422-018-0120-910.1038/s41422-018-0120-9 ↗
27. 10.1016/j.molcel.2022.01.00210.1016/j.molcel.2022.01.002 ↗
28. Sun J. · Elife. · 2018 · 7
29. 10.1016/j.celrep.2022.11165310.1016/j.celrep.2022.111653 ↗
30. 10.1038/s41580-022-00543-110.1038/s41580-022-00543-1 ↗
31. 10.1146/annurev-biochem-060310-17032810.1146/annurev-biochem-060310-170328 ↗
32. 10.1074/jbc.275.4.224710.1074/jbc.275.4.2247 ↗
33. 10.1016/j.molcel.2013.07.01410.1016/j.molcel.2013.07.014 ↗
34. 10.1038/nrm339410.1038/nrm3394 ↗
35. 10.1016/j.cell.2017.02.00410.1016/j.cell.2017.02.004 ↗
36. 10.1038/emboj.2008.30810.1038/emboj.2008.308 ↗
37. 10.1016/j.cmet.2017.11.00610.1016/j.cmet.2017.11.006 ↗
38. 10.1128/MCB.00106-1210.1128/MCB.00106-12 ↗
39. 10.1038/s41467-017-01567-410.1038/s41467-017-01567-4 ↗
40. 10.1016/j.cmet.2014.06.01410.1016/j.cmet.2014.06.014 ↗
41. 10.15252/embj.202211138910.15252/embj.2022111389 ↗
42. 10.1016/j.cell.2021.06.02810.1016/j.cell.2021.06.028 ↗
43. 10.1126/science.abg026910.1126/science.abg0269 ↗
44. 10.2174/138945012066619061812384610.2174/1389450120666190618123846 ↗
45. 10.1158/1541-7786.MCR-16-025610.1158/1541-7786.MCR-16-0256 ↗
46. 10.1007/978-0-387-70630-6_510.1007/978-0-387-70630-6_5 ↗
47. 10.3389/fonc.2022.84207210.3389/fonc.2022.842072 ↗
48. 10.1074/jbc.M109.09944010.1074/jbc.M109.099440 ↗
49. 10.1038/nprot.2007.27910.1038/nprot.2007.279 ↗