LAMTOR1

Official Full Name

late endosomal/lysosomal adaptor, MAPK and MTOR activator 1

Organism

Homo sapiens

GeneID

55004

Background

Enables GTPase binding activity and protein-membrane adaptor activity. Contributes to guanyl-nucleotide exchange factor activity and molecular adaptor activity. Involved in several processes, including cholesterol homeostasis; positive regulation of TORC1 signaling; and regulation of cholesterol transport. Located in lysosome. Part of FNIP-folliculin RagC/D GAP. Is active in Ragulator complex and lysosomal membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

p18; PDRO; C11orf59; p27RF-Rho; Ragulator1;

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Detailed Information

Recent Progress

The lysosomal adaptor protein Lamtor1 is an essential anchor of a scaffolding complex for the mTORC1 and MAPK pathways, which play an indispensable role in controlling cell growth and energy homeostasis. To elucidate the in vivo function of the Lamtor1-mediated pathway, researchers conditionally studied Lamtor1 in the mouse epidermis. Results showed that loss of Lamtor1 attenuated lysosome function, leading to accumulation of immature lysosomes and autophagosomes. Analyses of lysosome behavior revealed that Lamtor1 is required for functional interaction between lysosomes and target organelles including autophagosomes. These findings suggested that Lamtor1-mediated pathways can control lysosome-mediated catabolic processes, which are crucial for the development of mouse epidermis.

It is also known that LAMTOR1 is specifically localized to the surface of late lysosomes which serve as an anchor for the "Ragulator" complex. The Ragulator interacts with RagAB/CD GTPases and V-ATPase and plays crucial roles for activation of mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal surface. Activated mTORC1 organizes various cellular functions, for example, macromolecule biosynthesis, energy metabolism, autophagy, cell growth, responses to growth factors, and the trafficking and maturation of lysosomes. The Ragulator can also regulate a branch of the MAPK pathway by recruiting MEK1 to MP1/LAMTOR3. These findings suggested that LAMTOR1 creates a core platform for intracellular signaling pathways that function via late lysosomes (Fig.1).

Fig. 1. Effects of inhibitors of mTORC1 and MAPK pathways on interaction between lysosomes and autophagosomes. (Nada et al, 2014)

Another group of researchers showed that Lamtor1 is capable of forming an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase) and is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR(mechanistic target of rapamycin) resulted in defective M2 polarization and enhanced M1 polarization. Furthermore, it was identified that liver X receptor (LXR) serve as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. These findings demonstrated that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.

Accumulating evidence also indicated that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Investigators reported that UBE3A regulates mTORC1 signaling by targeting Lamtor1, which is a subunit of the Ragulator. UBE3A ubiquinates Lamtor1, resulting in its proteasomal degradation, and its deficiency in hippocampus of AS mice led to increased lysosomal localization of Lamtor1. Moreover, other members of the Ragulator-Rag complex displayed increased mTORC1 activity. LAMTOR1 down-regulation by siRNA in hippocampal CA1 neurons of AS mice reduces mTORC1 activity and improves long-term potentiation (LTP) along with dendritic spine maturation. These findings indicated that UBE3A-mediated regulation of Lamtor1 and subsequent mTORC1 signaling are critical for typical synaptic plasticity and dendritic spine development.

Interestingly, studies using mice with conditional knockout of mTORC1 component proteins gave conflicting results on the roles of mTORC1 in CD4+ T cells. Through investigation, researchers showed that Lamtor1-deficient CD4+ T cells exhibited marked reductions in proliferation, IL-2 production, mTORC1 activity, and expression of purine- and lipid-synthesis genes. Polarization of Th17 cells, but not Th1 and Th2 cells, diminished following the loss of Lamtor1. Lamtor1-deficient regulatory T cells survived ex vivo as long as wild-type regulatory T cells; however, they exhibited a marked loss of suppressive function and expression of signature molecules. These results indicated that Lamtor1 plays essential roles in CD4+ T cells, suggesting that Lamtor1 should be considered a novel therapeutic target in immune systems.

References:

Somanagae, T., Nada, S., Kitagawa, M., Takahashi, Y., Mori, S., & Oneyama, C., et al. (2013). The lysosomal signaling anchor p18/lamtor1 controls epidermal development by regulating lysosome-mediated catabolic processes. Journal of Cell Science, 126(16), 3575-3584.
Nada, S., Mori, S., Takahashi, Y., & Okada, M. (2014). P18/lamtor1: a late endosome/lysosome-specific anchor protein for the mtorc1/mapk signaling pathway. Methods in Enzymology, 535, 249.
Tetsuya, K., Shigeyuki, N., Noriko, T., Tatsusada, O., Satoshi, N., & Kang, S., et al. (2016). Polarization of m2 macrophages requires lamtor1 that integrates cytokine and amino-acid signals:. Nature Communications, 7, 13130.
Hayama, Y., Kimura, T., Takeda, Y., Nada, S., Koyama, S., & Takamatsu, H., et al. (2018). Lysosomal protein lamtor1 controls innate immune responses via nuclear translocation of transcription factor eb. Journal of Immunology, ji1701283.
Sun, J., Liu, Y., Jia, Y., Hao, X., Lin, W. J., & Tran, J., et al. (2018). Ube3a-mediated p18/lamtor1 ubiquitination and degradation regulate mtorc1 activity and synaptic plasticity. Elife, 7.
Hosokawa, T., Kimura, T., Nada, S., Okuno, T., Ito, D., & Kang, S., et al. (2017). Lamtor1 is critically required for cd4+ t cell proliferation and regulatory t cell suppressive function. Journal of Immunology, 199(6), 2008.

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