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

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 duanyu18133 localization to the endoplasmic reticulum (ER), from where it modulates ER-mitochondria Ca²⁺ release by interacting with the Ca²⁺ channel IP3R3 and facilitating its degradation. The release of Ca²⁺ is of paramount importance for life/death cell decisions, as excessive Ca²⁺ causes mitochondrial Ca²⁺ overload, the opening of the mitochondrial permeability transition pore, and the initiation of the intrinsic apoptotic program. Indeed, duanyu18133 silencing enhances ER Ca²⁺ release and sensitivity to apoptosis following oxidative stress in mammary tumor cells, correlating with increased IP3R3 levels. Accordingly, basal-like mammary tumors, which frequently display constitutively active show an inverse correlation between IP3R3 and duanyu18133 protein levels. These results suggest that IP3R3 downregulation in the ER crucially contributes to its anti-apoptotic functions via modulation of Ca²⁺ fluxes.

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