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OPINION

Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation

Abstract

B cells face multiple restrictions on glucose and energy metabolism. Their lineage-determining transcription factors repress glucose uptake and pentose phosphate pathway activity, while their low numbers of mitochondria and small cytoplasmic volume set narrow limits for mitochondrial ATP production and autophagy as alternative energy sources. During activation, B cells can balance temporary increases of energy expenditure. However, permanent hyperactivation of kinases, for instance, downstream of an autoreactive B cell receptor (BCR) or a transforming oncogene, can cause energy stress and cell death. Here, I propose that B cell-intrinsic restriction of ATP represents a safeguard to eliminate autoreactive or pre-malignant B cells. If the metabolic gatekeepers are compromised, influx of additional glucose may fuel permanent increases in metabolic demands and pathological B cell proliferation, driven by an autoreactive BCR or a transforming oncogene.

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Fig. 1: Gatekeeper I: control of glucose membrane transport.
Fig. 2: Gatekeeper II: control of ATP consumption by inhibitory phosphatases.
Fig. 3: Gatekeeper III: regulation of intracellular ROS by the PPP and mitochondrial dynamics.

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Acknowledgements

The author thanks L. N. Chan, Z. Chen, S. Shojaee, S. Swaminathan, G. Xiao, T. Sadras, G. Deb and other current and former members of his laboratory as well as E. Meffre (New Haven, CT), T. G. Graeber (Los Angeles, CA), A. Weiss and C. A. Lowell (San Francisco, CA), H. Jumaa (Ulm, Germany), A. Melnick (New York, NY) and N. Bottini (La Jolla, CA) for critical discussions and encouragement. M.M. is a Howard Hughes Medical Institute Faculty Scholar (HHMI-55108547) and acknowledges support by the Leukemia and Lymphoma Society (Scholar Award 1479–11), the Wellcome Trust (Senior Investigator Award WT101880) and the US National Cancer Institute (Outstanding Investigator Award R35CA197628).

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Nature Reviews Immunology thanks R. Chiarle, M. Luftig and other anonymous reviewer(s) for their contribution to the peer review of this work.

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M.M. developed the metabolic gatekeeper concept, researched the data and wrote the manuscript.

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Correspondence to Markus Müschen.

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Müschen, M. Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation. Nat Rev Immunol 19, 337–348 (2019). https://doi.org/10.1038/s41577-019-0154-3

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