Vps35-dependent recycling of Trem2 regulates microglial function
Abstract
Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11. When Vps35 is knocked down, Trem2 accumulated in the lysosomes but was not degraded. More importantly, Vps35 deficiency leads to excessive lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and IL-6 production, which can be abolished by Trem2 overexpression. Furthermore, R47H Trem2, an AD-associated mutant, failed to interact with Vps35 and became unstable compared with wild-type Trem2. Our study suggests that Vps35/retromer is responsible for recycling of Trem2 in the regulation of microglial function such as proinflammatory responses, whereas R47H mutation impairs Trem2 trafficking, which might contribute to AD.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
LANDO is required for the recycling of putative Aβ receptors (CD36, TREM2, and TLR4) from internalized endosomes to the plasma membrane.
“According to the receptor-recycling method we employed and established by others (Lucin et al., 2013; Yin et al., 2016), we found that LANDO is required for the recycling of putative Aβ receptors (CD36, TREM2, and TLR4) from internalized endosomes to the plasma membrane.”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Yin et al., 2016
Cites
<i>TREM2</i> Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020 · see citing works
Variant of <i>TREM2</i> Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · see citing works
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736 · see citing works
Mukherjee, S., Ghosh, R. K., & Maxfield, F. R. (1997) · Physiological Reviews · doi:10.1152/physrev.1997.77.3.759 · Cited by 1,299 · see citing works
Bouchon, A., Dietrich, J., & Colonna, M. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.10.4991 · Cited by 1,284 · cited 1× · see citing works
“Trem2 consists of a leading signal peptide, a single type V extracellular region containing 3 potential N-glycosylation sites, a transmembrane domain and a short cytoplasmic tail lacking signaling motifs.(1) Owing to its short cytoplasmic tail, Trem2 needed to transfer its signaling by Dap12, an adaptor protein,(2) wh…”
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798 · see citing works
TREMs in the immune system and beyond
Colonna, M. (2003) · Nature Reviews Immunology · doi:10.1038/nri1106 · Cited by 701 · see citing works
ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587 · see citing works
Association of DAP12 with Activating CD94/NKG2C NK Cell Receptors
Lanier, L. L., Corliss, B. C., Wu, J., & Phillips, J. H. (1998) · Immunity · doi:10.1016/s1074-7613(00)80574-9 · Cited by 560 · see citing works
Verghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220484110 · Cited by 556 · see citing works
TREM2 sustains microglial expansion during aging and response to demyelination
Poliani, P. L., Wang, Y., Fontana, E., Robinette, M. L., Yamanishi, Y., Gilfillan, S., & Colonna, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77983 · Cited by 525 · see citing works
Ren, M., Xu, G., Zeng, J., Lemos-Chiarandini, C. D., Adesnik, M., & Sabatini, D. D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6187 · Cited by 482 · see citing works
Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts
Paloneva, J., Kestilä, M., Wu, J., Salminen, A., Böhling, T., Ruotsalainen, V., Hakola, P., Bakker, A. B. H., Phillips, J. H., Pekkarinen, P., et al. (2000) · Nature Genetics · doi:10.1038/77153 · Cited by 460 · see citing works
Temkin, P. A., Lauffer, B. E. L., Jäger, S., Cimermančič, P., Krogan, N. J., & von Zastrow, M. (2011) · Nature Cell Biology · doi:10.1038/ncb2252 · Cited by 460 · see citing works
Model‐guided microarray implicates the retromer complex in Alzheimer's disease
Small, S. A., Kent, K., Pierce, A., Leung, C., Kang, M. S., Okada, H., Honig, L., Vonsattel, J., & Kim, T. (2005) · Annals of Neurology · doi:10.1002/ana.20667 · Cited by 440 · see citing works
TREM and TREM-like receptors in inflammation and disease
Ford, J. W., & McVicar, D. W. (2009) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.01.009 · Cited by 434 · see citing works
Takahashi, K., Prinz, M., Stagi, M., Chechneva, O., & Neumann, H. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040124 · Cited by 414 · see citing works
Rayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-19 · Cited by 404 · see citing works
Chen, W., Feng, Y., Chen, D., & Wandinger‐Ness, A. (1998) · Molecular Biology of the Cell · doi:10.1091/mbc.9.11.3241 · Cited by 387 · see citing works
Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.579 · Cited by 374 · cited 1× · see citing works
“Many mutations of Trem2 have been involved in several neurodegenerative diseases.(6,10,13,41,42) Recently, 2 independent groups investigated how Trem2 missense mutations affected Trem2 func-”
Lucin, K. M., O’Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.046 · Cited by 374 · see citing works
Jiang, T., Tan, L., Zhu, X.-C., Zhang, Q.-Q., Cao, L., Tan, M.-S., Gu, L.-Z., Wang, H.-F., Ding, Z.-Z., Zhang, Y.-D., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.164 · Cited by 320 · see citing works
The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E
Bailey, C. C., DeVaux, L. B., & Farzan, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677286 · Cited by 303 · see citing works
Functional architecture of the retromer cargo-recognition complex
Hierro, A., Rojas, A. L., Rojas, R., Murthy, N., Effantin, G., Kajava, A. V., Steven, A. C., Bonifacino, J. S., & Hurley, J. H. (2007) · Nature · doi:10.1038/nature06216 · Cited by 297 · see citing works
<i>TREM2</i>Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis
Cady, J., Koval, E. D., Benitez, B. A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R. H., Ravits, J., Simpson, E., Appel, S. H., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6237 · Cited by 262 · see citing works
Cell fate regulation by coupling mechanical cycles to biochemical signaling pathways
Viola Vogel, B., & Sheetz, M. P. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.01.002 · Cited by 261 · see citing works
Endocytosis: clathrin-mediated membrane budding.
Ungewickell, E., & Hinrichsen, L. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.05.003 · Cited by 257 · see citing works
TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice
Frank, S., Burbach, G. J., Bonin, M., Walter, M., Streit, W., Bechmann, I., & Deller, T. (2008) · Glia · doi:10.1002/glia.20710 · Cited by 247 · see citing works
Sharma, D., Choudhury, A., Singh, R. D., Wheatley, C. L., Marks, D. L., & Pagano, R. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210457200 · Cited by 218 · see citing works
Mitchell, H., Choudhury, A., Pagano, R. E., & Leof, E. B. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-03-0245 · Cited by 215 · see citing works
Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L., Liu, T., Lassen, C. F., Meissner, E., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.12.009 · Cited by 205 · see citing works
Sessa, G., Podini, P., Mariani, M., Meroni, A., Spreafico, R., Sinigaglia, F., Colonna, M., Panina, P., & Meldolesi, J. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03729.x · Cited by 165 · see citing works
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.005 · Cited by 158 · see citing works
Zhong, L., Chen, X.-F., Zhang, Z.-L., Wang, Z., Shi, X.-Z., Xu, K., Zhang, Y.-W., Xu, H., & Bu, G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.645986 · Cited by 133 · see citing works
Melchior, B., Garcia, A., Hsiung, B., Lo, K. M., Doose, J. M., Thrash, J. C., Stalder, A. K., Staufenbiel, M., Neumann, H., & Carson, M. J. (2010) · ASN NEURO · doi:10.1042/an20100010 · Cited by 133 · see citing works
EHD1 Interacts with Retromer to Stabilize SNX1 Tubules and Facilitate Endosome‐to‐Golgi Retrieval
Gokool, S., Tattersall, D., & Seaman, M. N. J. (2007) · Traffic · doi:10.1111/j.1600-0854.2007.00652.x · Cited by 131 · see citing works
Kiialainen, A., Hovanes, K., Paloneva, J., Kopra, O., & Peltonen, L. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.09.007 · Cited by 114 · see citing works
McGough, I. J., Steinberg, F., Gallon, M., Yatsu, A., Ohbayashi, N., Heesom, K. J., Fukuda, M., & Cullen, P. J. (2014) · Journal of Cell Science · doi:10.1242/jcs.156299 · Cited by 102 · see citing works
Park, J., Ji, I. J., An, H. J., Kang, M., Kang, S., Kim, D., & Yoon, S. (2015) · Traffic · doi:10.1111/tra.12264 · Cited by 88 · see citing works
Murcia, J. D. G., Schmutz, C., Munger, C., Perkes, A. D., Gustin, A. J., Peterson, M., Ebbert, M., Norton, M. C., Tschanz, J. T., Munger, R. G., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.004 · Cited by 54 · see citing works
Prada, I., Naum-Onganı́a, G., Buonsanti, C., Panina‐Bordignon, P., & Meldolesi, J. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.03.058 · Cited by 49 · see citing works
A novel mechanism underlying pathogenesis of Down syndrome
Wang, X., Zhao, Y., Zhang, X., Zhou, Y., Ranscht, B., Gage, F. H., Mobley, W. C., Zhang, Y., Lipton, S. A., Hong, W., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-s1-o23 · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
To degrade or not to degrade: Mechanisms and significance of endocytic recycling
Cullen, P. J., & Steinberg, F. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0053-7 · Cited by 590 · see citing works
Heckmann, B. L., Teubner, B. J. W., Tummers, B., Boada-Romero, E., Harris, L., Yang, M., Guy, C. S., Zakharenko, S. S., & Green, D. R. (2019) · Cell · doi:10.1016/j.cell.2019.05.056 · Cited by 503 · see citing works
“According to the receptor-recycling method we employed and established by others (Lucin et al., 2013; Yin et al., 2016), we found that LANDO is required for the recycling of putative Aβ receptors (CD36, TREM2, and TLR4) from internalized endosomes to the plasma membrane.”
The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244 · see citing works
Yao, R., Pan, R., Shang, C., Li, X., Cheng, J., Xu, J., & Li, Y. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00986 · Cited by 79 · see citing works
Retromer dysfunction at the nexus of tauopathies
Carosi, J. M., Denton, D., Kumar, S., & Sargeant, T. J. (2021) · Cell Death & Differentiation · doi:10.1038/s41418-020-00727-2 · Cited by 16 · see citing works
- Authors
- Yin, J., Liu, X., He, Q., Zhou, L., Yuan, Z., & Zhao, S.
- Affiliations
- Chinese Academy of Sciences (CN)
- Qingdao Mental Health Center (CN)
- Corresponding author
- Zhao, Siqi
- Venue
- Traffic
- Publisher
- Wiley
- Published
- 2016-11
- Volume
- 17
- Issue
- 12
- Pages
- 1286-1296
- ISSN
- 1398-9219 (ISSN-L)
- 1600-0854
- OpenAlex
- W2525887216
- Cited by
- 90
- References
- 43
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 19 · 2022: 13 · 2021: 7 · 2020: 11 · 2019: 7 · 2018: 11 · 2017: 4
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Traffic (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81125010, 81030025, 81600997)
- Chinese Academy of Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- TREM2, VPS35, retromer complex, microglia, protein recycling, endocytosis, clathrin-mediated endocytosis, lysosomal accumulation, Alzheimer's disease, lipopolysaccharide, inducible nitric oxide synthase, interleukin-6, neuroinflammation, protein trafficking
- MeSH terms
- Alzheimer Disease, Animals, Cell Membrane, Endocytosis, HeLa Cells, Humans, Lipopolysaccharides, Lysosomes, Membrane Glycoproteins, Mice, Inbred C57BL, Mutation, Phagocytosis, Receptors, Immunologic, Interleukin-6, Microglia, Protein Transport, Vesicular Transport Proteins, Mice, Nitric Oxide Synthase Type II, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
