Inhibition of InsP3 receptor signalling induces autophagy

Chehab, Tala; Rietdorf, Katja; Parys, Jan; Bultynck, Geert and Bootman, Martin (2014). Inhibition of InsP3 receptor signalling induces autophagy. In: 13th International Meeting of the European Calcium Society, 13-17 Sep 2014, Aix-en-Provence, France.


Macroautophagy (autophagy) is an important process for cell survival and homeostasis that involves degradation of aggregated or misfolded proteins, dysfunctional organelles and pathogens through a lysosomal pathway. Autophagy occurs as a housekeeping process, and is greatly up-regulated in response to nutrient stress. Recent work has suggested that intracellular Ca2+ signals can positively and negatively regulate autophagic flux. Exactly how Ca2+ signals switch cells between pro-autophagic and antiautophagic states is not clear. It is likely that the source and characteristics of Ca2+ signals are critical in determining cellular responses. One source of Ca2+ signals that regulate autophagic flux is inositol 1,4,5-trisphosphate receptors (IP3Rs). This study examined the effect of inhibiting Ca2+ release from IP3Rs on autophagic flux, and compared the magnitude of autophagy following IP3R inhibition with that evoked by starvation and rapamycin (an mTOR inhibitor). HeLa cells stably expressing GFP-tagged LC3 responded to rapamycin with a significantly enhanced autophagic flux, in a time- and dose-dependent manner. Similarly, nutrient starvation induced autophagy in a timedependent manner. Expression of an IP3 5’-phosphatase evoked a substantial increase in autophagic flux that was comparable to rapamycin and nutrient starvation. The expression of IP3 5’-phosphatase significantly reduced cellular Ca2+ signals evoked by application of the IP3-generating hormone, histamine. These data indicate that the activation of IP3Rs is critical to prevent induction of autophagy. Loss of IP3R function triggers autophagy with a similar magnitude to that evoked by pharmacological inhibition of mTOR and nutrient starvation.

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