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

Proc Natl Acad Sci U S A. 2021 Sep 28;118(39):e2101268118. doi: 10.1073/pnas.2101268118.

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 up-regulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed up-regulation of IL-6 transcription and secretion compared to wild-type 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 wild-type cells. Treatment with anti-IL-6 (αIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2+/- mice while reducing PSAT1 expression. These data reveal a mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity.

Keywords: interleukin 6; lymphangioleiomyomatosis; mTORC1; phosphoserine aminotransferase 1 (PSAT1); tuberous sclerosis complex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Serine / metabolism*
  • Transaminases / genetics
  • Transaminases / metabolism*
  • Tuberous Sclerosis Complex 2 Protein / genetics
  • Tuberous Sclerosis Complex 2 Protein / metabolism*
  • Tuberous Sclerosis Complex 2 Protein / physiology

Substances

  • Interleukin-6
  • TSC2 protein, human
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Serine
  • Transaminases
  • phosphoserine aminotransferase
  • Mechanistic Target of Rapamycin Complex 1