Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells

Wang, J.; Filippakis, H.; Hougard, T.; Du, H.; Ye, C.; Liu, H.-J.; Zhang, L.; Hindi, K.; Bagwe, S.; Nijmeh, J.; Asara, J. M.; Shi, W.; El-Chemaly, S. Y.; Henske, E. P.; Lam, H. C.

doi:10.1101/2021.05.17.444471

bioRxiv · 10.1101/2021.05.17.444471

Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells

Wang, J.·Filippakis, H.·Hougard, T.·Du, H.·Ye, C.·Liu, H.-J.·Zhang, L.·Hindi, K.·Bagwe, S.·Nijmeh, J.·Asara, J. M.·Shi, W.·El-Chemaly, S. Y.·Henske, E. P.·Lam, H. C.

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Abstract

Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2. Cytokine profiling of TSC2-deficient LAM patient-derived cells revealed striking upregulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed upregulation of IL-6 transcription and secretion compared to wildtype cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification. U-13C glucose tracing revealed that IL-6 knockout reduced 3-phosphoserine and serine production in TSC2-deficient cells, implicating IL-6 in de novo serine metabolism. IL-6 knockout reduced expression of phosphoserine aminotransferase 1 (PSAT1), an essential enzyme in serine biosynthesis. Importantly, recombinant IL-6 treatment rescued PSAT1 expression in the TSC2-deficient, IL-6 knockout clones selectively and had no effect on wildtype cells. Treatment with anti-IL-6 (aIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2+/- mice, while reducing PSAT1 expression. These data reveal a novel mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity. ClassificationMajor category: Biological Sciences Minor category: Cell Biology

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Wang, J., Filippakis, H., Hougard, T., Du, H., Ye, C., Liu, H.-J., Zhang, L., Hindi, K., Bagwe, S., Nijmeh, J., Asara, J. M., Shi, W., El-Chemaly, S. Y., Henske, E. P., Lam, H. C.. 2021-05-17. Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells. https://doi.org/10.1101/2021.05.17.444471

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