STAT3 localizes to the ER, acting as a gatekeeper for ER-mitochondrion Ca2+ fluxes and apoptotic responses

Abstract

STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcriptional activator and as a non-canonical regulator of energy metabolism and mitochondrial functions. While both activities are required for cell transformation downstream of different oncogenic stimuli, they rely on different post-translational activating events, namely phosphorylation on either Y705 (nuclear activities) or S727 (mitochondrial functions). Here, we report the discovery of the unexpected STAT3 localization to the endoplasmic reticulum (ER), from where it modulates ER-mitochondria Ca release by interacting with the Ca channel IP3R3 and facilitating its degradation. The release of Ca is of paramount importance for life/death cell decisions, as excessive Ca causes mitochondrial Ca overload, the opening of the mitochondrial permeability transition pore, and the initiation of the intrinsic apoptotic program. Indeed, STAT3 silencing enhances ER Ca release and sensitivity to apoptosis following oxidative stress in STAT3-dependent mammary tumor cells, correlating with increased IP3R3 levels. Accordingly, basal-like mammary tumors, which frequently display constitutively active STAT3, show an inverse correlation between IP3R3 and STAT3 protein levels. These results suggest that STAT3-mediated IP3R3 downregulation in the ER crucially contributes to its anti-apoptotic functions via modulation of Ca fluxes.

Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

“…Signal Transducer and Activator of Transcription 3 in the Endoplasmic Reticulum. STAT3 has recently been found to translocate to the ER (Avalle et al, 2019), where it interacts with the calcium channel inositol 1,4,5-trisphosphate receptor, type 3 (IP3R3), facilitating its degradation, possibly through the ubiquitin E3 ligase FBXL2 (Kuchay et al, 2017). The decrease in IP3R3 reduces calcium efflux from ER to the cytoplasm and mitochondria.…”

STAT 3 ‐dependent analysis reveals PDK 4 as independent predictor of recurrence in prostate cancer

“…The deletion of Stat3 in prostate epithelial cells in a loss of Pten PCa mouse model leads to increased tumor growth and early death (Pencik et al , ). It is well established that STAT3 is able to influence the activity of mitochondria, the electron transport chain (ETC), and the ER in its pY form as a transcription factor, but also via direct binding to these cell compounds in its serine‐phosphorylated (pS) form (Wegrzyn et al , ; Poli & Camporeale, ; Avalle et al , ; Huynh et al , ). On the one hand, pY‐STAT3 is associated with increase in glycolysis and the suppression of the ETC by its function as transcription factor.…”

STAT3-dependent systems-level analysis revealsPDK4as an independent predictor of biochemical recurrence in prostate cancer

“…The deletion of Stat3 in prostate epithelial cells in a loss of Pten PCa mouse model leads to increased tumor growth and early death (Pencik et al, 2015). It is well established that STAT3 is able to control the activity of mitochondria, the electron transport chain (ETC) and the ER both via transcriptional control and via direct binding to these cell compounds (Avalle et al, 2018, Huynh et al, 2019, Poli and Camporeale, 2015, Wegrzyn et al, 2009). On the one hand, STAT3 expression is associated with increase in glycolysis and the suppression of the ETC (Wegrzyn et al, 2009, Huynh et al, 2019.…”