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TMEM 55B contributes to lysosomal homeostasis and amino acid–induced mTORC 1 activation
Abstract
Mammalian/mechanistic target of rapamycin complex 1 (mTORC 1) responds to growth factors and nutrient availability. Amino acids induce the recruitment of mTORC 1 to the lysosomal membrane and its consequent activation, but the molecular mechanism of such activation has remained unclear. We have now examined the role of TMEM 55B, a lysosomal protein of unknown molecular function, in this process on the basis of the results of proteomics and immunofluorescence analyses showing that TMEM 55B interacts with many proteins that participate in mTORC 1 activation including components of the vacuolar‐type proton ATP ase (V‐ATP ase) and Ragulator complexes at the lysosomal membrane. The amino acid–induced phosphorylation of the mTORC 1 substrates S6K and 4E‐BP was attenuated in TMEM 55B‐depleted cells compared with control cells. Depletion of TMEM 55B was also found to evoke lysosomal stress as showed by translocation of the transcription factor TFEB to the nucleus. Furthermore, recruitment of the V1 domain subcomplex of V‐ATP ase to lipid rafts was abrogated in TMEM 55B‐depleted cells. Collectively, our results suggest that TMEM 55B contributes to assembly of the V‐ATP ase complex in lipid rafts of the lysosomal membrane and to subsequent activation of mTORC 1.
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TMEM55B modulates lysosome function.
“TMEM55B is localized to the late endosome and lysosome7, and has been shown to impact lysosome function23, 28.”
From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [23]
TMEM55B impacts lysosome function.
“TMEM55B is localized to the late endosome and lysosome7, and has been shown to impact lysosome function23, 28.”
From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [23]
Depletion of TMEM55B in mice is embryonic lethal.
“Since depletion of TMEM55B in mice was shown to be embryonic lethal34, we decided to use zebrafish as model system.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [34]
TMEM55B regulates autophagosome-lysosome fusion, lysosomal repair, and TFE3 nuclear translocation under stress, interacts with amino-acid sensing complexes, and modulates cholesterol metabolism via PI(4,5)P2 phosphatase activity.
“TMEM55B also regulates autophagosome-lysosome fusion, lysosomal repair, and TFE3 nuclear translocation under stress (Jeong et al. 2024), interacts with amino-acid sensing complexes (Hashimoto et al. 2018), and modulates cholesterol metabolism via PI(4,5)P2 phosphatase activity (Qin et al. 2020).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Hashimoto et al. 2018
TMEM55B associates with V-ATPase/Ragulator to regulate mTORC1 and controls PI(4,5)P2-dependent LDLR and cholesterol metabolism.
“TMEM55B associates with V-ATPase/Ragulator to regulate mTORC1 (Hashimoto et al. 2018) and controls PI(4,5)P2-dependent LDLR and cholesterol metabolism (Qin et al. 2020).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Hashimoto et al. 2018
Knockout of TMEM55B leads to lysosomal stress and loss of vATPase function related to lysosomal acidification.
“Knockout of TMEM55B leads to lysosomal stress and loss of vATPase function which is related to the acidification of lysosomes (Hashimoto et al., 2018).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Hashimoto et al., 2018
TMEM55B can inhibit TFEB nuclear translocation, thus suppressing expression of lysosomal genes.
“Interestingly, while TMEM55B expression is dependent on TFEB (Willett et al., 2017), TMEM55B can actually inhibit TFEB nuclear translocation (Hashimoto et al., 2018) thus suppressing expression of lysosomal genes.”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Hashimoto et al., 2018
TMEM55B is implicated in direct regulation of endo-lysosomal acidification, potentially independently of its trafficking functions.
“TMEM55B is also implicated in direct regulation of endo-lysosomal acidification, potentially independently of its trafficking functions (Hashimoto et al., 2018;Takemasu et al., 2019).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Hashimoto et al., 2018
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Sorted by citations
TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress
Jeong, E., Willett, R., Rissone, A., La Spina, M., & Puertollano, R. (2024) · Nature Communications · doi:10.1038/s41467-023-44316-6 · Cited by 25
Qin, Y., Ting, F., Kim, M. J., Strelnikov, J., Harmon, J., Gao, F., Dose, A., Teng, B.-B., Alipour, M. A., Yao, Z., et al. (2020) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.120.314033 · Cited by 18
Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12
Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease
Odfalk, K. F., Wickline, J. L., Smith, S., Dobrowolski, R., & Hopp, S. C. (2024) · Hippocampus · doi:10.1002/hipo.23586 · Cited by 2
TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models
Roy, B., Contu, V. R., Jeziorek, M., Friedman, W. J., & Wong, C.-O. (2026) · doi:10.64898/2026.10.21.760809
TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles
Rudnik, S., Li, C. H., Gottschling, D.-C., Veh, A., Barbosa, D. J., Richter, J., Stroobants, S., Schuster, B., Beck, I. M., Sedlack, R., et al. (2026) · doi:10.64898/2026.10.27.762112
Metadata
- Authors
- Hashimoto, Y., Shirane, M., & Nakayama, K. I.
- Affiliations
- Department of Molecular and Cellular Biology Medical Institute of Bioregulation Kyushu University Fukuoka Japan
- ORCID
- Nakayama, Keiichi I.
- Venue
- Genes to Cells
- Publisher
- Wiley
- Published
- 2018-04-11
- Volume
- 23
- Issue
- 6
- Pages
- 418-434
- ISSN
- 1356-9597
- 1365-2443
- Cited by
- 46
- References
- 5
- Language
- en
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (KAKENHI 17H06301, 25221303, and 26640080)
- Japan Society for the Promotion of Science
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