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The role of LKB1 spliceoforms in iTreg-Th17 plasticity and their interactions with PKCθ and SIRT1 downstream of IL-6 signaling

Abstract
Following activation, CD4 T cells undergo metabolic and transcriptional changes as they respond to external cues and differentiate into T helper (Th) cells. T cells exhibit plasticity between Th phenotypes in highly inflammatory environments, such as colitis, in which high levels of IL-6 promote plasticity between regulatory T (Treg) cells and Th17 cells. Protein Kinase C theta (PKCθ) is a T cell-specific serine/threonine kinase that promotes Th17 differentiation while negatively regulating Treg differentiation. Liver kinase B1 (LKB1), also a serine/threonine kinase and encoded by Stk11, is necessary for Treg survival and function. Stk11 can be alternatively spliced to produce a short variant (Stk11S) by transcribing a cryptic exon. However, the contribution of Stk11 splice variants to Th cell differentiation has not been previously explored. Here we show that in Th17 cells, the heterogeneous ribonucleoprotein, hnRNPLL, mediates Stk11 splicing into its short splice variant, and that Stk11S expression is diminished when Hnrnpll is depleted using siRNA knock-down approaches. We further show that PKCθ regulates hnRNPLL and, thus, Stk11S expression in Th17 cells. We provide additional evidence that iTreg exposure to IL-6 culminates in Stk11 splicing downstream of PKCθ. Altogether our data reveal a yet undescribed outside-in signaling pathway initiated by IL-6, that acts through PKCθ and hnRNPLL, to regulate Stk11 splice variants and induce Th17 cell differentiation. Furthermore, we show for the first time, that this pathway can also be induced in iTregs exposed to IL-6, providing mechanistic insight into iTreg phenotypic stability and iTreg to Th17 cell plasticity. Sirtuin 1 (Sirt1) plays a crucial role in metabolism and inflammatory responses. Sirt1 is a deacetylase that can regulate different transcription factors important for modulating immune responses. Sirt1 has been shown to increase iTreg conversion to Th17 cells by deacetylating the Foxp3 transcription factor in iTregs. LKB1, encoded by Stk11, has been identified as a mediator of Treg induction and function through its effects on TSDR methylation and metabolism. Sirt1 has been shown to activate LKB1, but the molecular mechanisms of these signaling pathways are not known. Our data suggest Stk11 splicing may lie at the heart of iTreg responses to IL-6 exposure and may represent a unique target for developing stable, cell-based iTreg therapies. Examining the contribution of Sirt1 to this process may provide additional insight as to how LKB1 isoforms regulate iTreg-Th17 cell fate decisions.
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