WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity
Abstract
WAVE-ing T cell activation off: The WAVE regulatory complex (WRC) is a pentameric complex that regulates actin cytoskeleton dynamics. The precise role for the WRC in immunity has not been established, although recent work has implicated WRC components such as HEM1 in certain human immunodeficiencies. Liu et al. characterized mice with a conditional knockout of the WRC constituent WAVE2 (see the Perspective by Hambleton). These mice exhibited progressive severe autoimmune and inflammatory disease associated with the activation and accelerated differentiation of T cells. WAVE2's suppression of T cell activation was not mediated by the T cell receptor but rather by its inhibition of mammalian target of rapamycin (mTOR) binding to RAPTOR and RICTOR. Accordingly, the autoimmune phenotype of these mice could be ameliorated by pharmacological inhibitors of mTOR signaling. Science , this issue p. eaaz4544 ; see also p. 1309
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Physical interaction between WRC and mTORC subunits was observed.
“physical interaction between WRC and mTORC subunits was observed”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [41]
HEM1 deficiency reduces mTORC activity.
“in vitro data suggesting that HEM1 deficiency reduces mTORC activity [8, 41].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [41]
WAVE2 suppressed mTORC1 and mTORC2 activity in immunoprecipitation and in vitro kinase studies.
“Immunoprecipitation and in vitro kinase studies showed that WAVE2 suppressed mTORC1 and mTORC2 activity [41].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [41]
Physical interaction between WRC and mTORC subunits suggests direct modulation of kinase or actin polymerization activity.
“suggesting direct modulation of kinase or actin polymerization activity [8, 41].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [41]
Numerous Hem1-deficient mouse models demonstrated systemic autoimmunity and inflammation parallel to that seen in patients, including splenomegaly, immune complex lupus glomerulonephritis, elevated proinflammatory markers (IL-6, IFNγ, and MRP8/14), and autoreactive plasmablasts with elevated serum dsDNA autoantibodies.
“Numerous Hem1-deficient mouse models demonstrated systemic autoimmunity and inflammation parallel to that seen in patients, including splenomegaly, immune complex lupus glomerulonephritis, elevated proinflammatory markers (IL-6, IFNγ, and MRP8/14), and autoreactive plasmablasts with elevated serum dsDNA autoantibodies [9, 41].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [41]
T cell-specific Wave2 knockout mice displayed autoimmunity and cytokine hypersecretion similar to patients.
“a model of T cell–specific Wave2 knockout in mice produced the opposite effect; these mice displayed autoimmunity and cytokine hypersecretion similar to patients”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [41]
In T cell-specific Wave2 knockout mice, loss of WRC components resulted in enhanced mTORC1 and mTORC2 activity.
“loss of WRC components resulted in enhanced mTORC1 and mTORC2 activity in mice [41].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [41]
Cites
Bengsch, B., Johnson, A. L., Kurachi, M., Odorizzi, P. M., Pauken, K. E., Attanasio, J., Stelekati, E., McLane, L. M., Paley, M. A., Delgoffe, G. M., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.008 · Cited by 868 · cited 1× · see citing works
“Thus, these aberrations appear to reflect highmTOR activity as is consistent with the known role for chronic mTOR activation in promoting PD-1 up-regulation and downstreammetabolic changes that engender T cell exhaustion (27).”
BackgroundScharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R. E., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.009 · Cited by 848 · see citing works
Kim, K. S., Marcogliese, P. C., Yang, J., Callaghan, S. M., Resende, V., Abdel-Messih, E., Marras, C., Visanji, N. P., Huang, J., Schlossmacher, M. G., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718946115 · Cited by 111 · see citing works
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HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions
Cook, S., Lenardo, M. J., & Freeman, A. F. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01327-0 · Cited by 24 · see citing works
The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Liu, M., Zhang, J., Pinder, B. D., Liu, Q., Wang, D., Yao, H., Gao, Y., Toker, A., Gao, J., Peterson, A., Qu, J., & Siminovitch, K. A.
- Affiliations
- Mount Sinai Hospital (CA)
- Lunenfeld-Tanenbaum Research Institute (CA)
- University Health Network (CA)
- Wenzhou Medical University (CN)
- McGill University (CA)
- Corresponding author
- Liu, Ming
- Zhang, Jinyi
- Qu, Jia
- Siminovitch, Katherine A.
- ORCID
- Venue
- Science
- Published
- 2021-03-26
- Volume
- 371
- Issue
- 6536
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3137645650
- Cited by
- 53
- References
- 3
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 2 · 2023: 11 · 2022: 20 · 2021: 1
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (148457, FDN 148457)
- Canada Research Chairs
- Sherman Family Chair in Genomic Medicine
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- WAVE2, mTOR signaling, T cell homeostasis, autoimmunity, raptors, Rictor, T cell metabolism, T cell activation, inhibitory receptors, mitochondrial function, T cell survival, mTOR inhibitors, T cell differentiation
- MeSH terms
- Regulatory-Associated Protein of mTOR, Rapamycin-Insensitive Companion of mTOR Protein, Animals, Autoimmune Diseases, Cell Differentiation, Homeostasis, Immunologic Deficiency Syndromes, Lymphocyte Activation, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, Autoimmunity, Mice, Knockout, Sirolimus, Proto-Oncogene Proteins c-akt, Wiskott-Aldrich Syndrome Protein Family, Mice, TOR Serine-Threonine Kinases, Transcriptome
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