Inhibition of InsP₃ receptor signalling induces autophagy

Chehab, Tala; Rietdorf, Katja; Parys, Jan B.; Bultynck, Geert and Bootman, Martin D. (2014). Inhibition of InsP₃ receptor signalling induces autophagy. In: Calcium Signalling: The Next Generation, 9-10 Oct 2014, London, UK.

URL: http://www.biochemistry.org/

Abstract

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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