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Phosphorylation of TMEM55B by Erk/MAPK regulates lysosomal positioning
Abstract
TMEM55B is first identified as phosphatidylinositol-4,5-P24-phosphatases (PtdIns-4,5-P24-phosphatases) that catalyse dephosphorylation of PtdIns-4,5-P2 to PtdIns-5-P. We demonstrate for the first time that TMEM55B is phosphorylated by Erk/MAPK and that this mechanism participates in regulation of lysosomal clustering. Exposure of RAW264.7 macrophages to various stimuli induces phosphorylation of TMEM55B on Ser76 and Ser169, sites corresponding to consensus sequences (PX(S/T)P) for phosphorylation by MAPK. Of these stimuli, Toll-like receptor ligands most strongly induce TMEM55B phosphorylation, and this is blocked by the MEK1/2 inhibitor U0126. However, phosphorylation does not impact intrinsic phosphatase activity of TMEM55B. TMEM55B has recently been implicated in starvation induced lysosomal translocation. Amino acid starvation induces perinuclear lamp1 clustering in RAW264.7 macrophages, which was attenuated by shRNA-mediated knock-down or CRISPR/Cas9-mediated knock-out of TMEM55B. Cells exposed to U0126 also exhibit attenuated lamp1 clustering. Overexpression of TMEM55B but not TMEM55A notably enhances lamp1 clustering, with TMEM55B mutants (lacking phosphorylation sites or mimicking the phosphorylated state) exhibiting lower and higher efficacies (respectively) than wild-type TMEM55B. Collectively, results suggest that phosphorylation of TMEM55B by Erk/MAPK impacts lysosomal dynamics.
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TMEM55B can undergo reversible phosphorylation and is S-palmitoylated.
“TMEM55B can undergo reversible phosphorylation and is S-palmitoylated (Rudnik et al., 2022;Takemasu et al., 2019), suggesting a complex regulation of the protein's function by posttranslational modifications.”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Takemasu et al., 2019
JIP4-mediated retrograde transport of lysosomes facilitates interaction and fusion between autophagosomes and lysosomes, resulting in degradation of autophagosomal content and restoration of energy homeostasis.
“JIP4-mediated retrograde transport of lysosomes facilitates interaction and fusion between autophagosomes and lysosomes, resulting in degradation of autophagosomal content and restoration of energy homeostasis7–9.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [8]
Post-translational modifications, including S-palmitoylation and Erk/MAPK-mediated phosphorylation, modulate TMEM55B function.
“Post-translational modifications, including S-palmitoylation and Erk/MAPK-mediated phosphorylation, further modulate TMEM55B function (Takemasu et al. 2019).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Takemasu et al. 2019
S-palmitoylation regulates TMEM55B trafficking, while ERK/MAPK-mediated phosphorylation controls perinuclear clustering.
“S-palmitoylation regulates its trafficking (Rudnik et al. 2022), while ERK/MAPK-mediated phosphorylation controls perinuclear clustering (Takemasu et al. 2019).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Takemasu et al. 2019
Overexpression of TMEM55B may not be sufficient without altering post-translational processes that regulate TMEM55B function such as phosphorylation.
“These data suggest that early defects in endo-lysosomal function in 5-month-old 5XFAD mice herein may not be driven by transcriptional regulation but instead by post-translational processes and thus overexpression of TMEM55B may not be sufficient without altering post-translational processes that regulate TMEM55B function such as phosphorylation (Takemasu et al., 2019).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Takemasu et al., 2019
TMEM55B regulation of lysosome positioning and trafficking is independent from its phosphatase function.
“TMEM55B regulates lysosome positioning and trafficking via interaction with the JIP4 motor protein adapter (Willett et al., 2017) independently from its phosphatase function (Takemasu et al., 2019) but dependent on S-palmitoylation (Rudnik et al., 2022).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Takemasu et al., 2019
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 Takemasu et al., 2019
Citations
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Transmembrane Protein 55B Is a Novel Regulator of Cellular Cholesterol Metabolism
Medina, M. W., Bauzon, F., Naidoo, D., Theusch, E., Stevens, K., Schilde, J., Schubert, C., Mangravite, L. M., Rudel, L. L., Temel, R. E., et al. (2014) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.302806 · Cited by 24
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Sorted by citations
RAF-MEK-ERK pathway in cancer evolution and treatment
Ullah, R., Yin, Q., Snell, A. H., & Wan, L. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.05.010 · Cited by 553
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
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
- Takemasu, S., Nigorikawa, K., Yamada, M., Tsurumi, G., Kofuji, S., Takasuga, S., & Hazeki, K.
- Affiliations
- Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Pathology and Immunology, Akita University School of Medicine, Akita, Japan
- Venue
- The Journal of Biochemistry
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-04-09
- Volume
- 166
- Issue
- 2
- Pages
- 175-185
- ISSN
- 0021-924X
- 1756-2651
- Cited by
- 27
- References
- 2
- Language
- en
- Funders
- Innovative Researchers and Academic Knowledge Users
- HIRAKU
- JSPS
- KAKENHI (JP18K07233)
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