Nck1 deficiency improves pancreatic β cell survival to diabetes-relevant stresses by modulating PERK activation and signaling.

Increasing evidence strongly supports a critical role for PERK in regulating pancreatic β cell function. In agreement, we previously reported that enhancing PERK basal activity, by silencing the SH domain-containing adaptor protein Nck1 in pancreatic β cells, increased insulin content in a PERK-dependent manner. Here we report that Nck1-deficient MIN6 cells display normal overall morphology while as expected increased number of secretory granules. Furthermore, we demonstrate that cell survival to diabetes-relevant stresses is increased, while cell viability in response to chemical endoplasmic reticulum (ER) stress inducers is not changed. In agreement, PERK activation in Nck1-depleted MIN6 cells exposed to palmitate was significantly reduced while it remained strongly induced by the ER stress inducer thapsigargin. Interestingly, silencing Nck1 in MIN6 cells results in increased PERK basal activity and expression of the PERK downstream target sestrin2, which promotes autophagy by attenuating mTORC1 activation through AMPK-dependent and -independent mechanisms. Accordingly, activated AMPK was increased, mTORC1 signaling decreased, and autophagy markers increased in Nck1-silenced MIN6 cells. Increased autophagy was recapitulated in Nck1(-/-) mice pancreatic β cells. In addition, basal levels of the PERK substrate Nrf2 and its antioxidant gene targets (HO-1 and Nqo1) were upregulated in Nck1-silenced MIN6 cells, revealing an active PERK-Nrf2 signaling in these cells. Finally, Akt activation was increased in Nck1-silenced MIN6 cells. Altogether, this study demonstrates that Nck1 silencing in pancreatic β cells promotes PERK activation and signaling to protect β cells against pathological stresses. These findings further provide new perspectives to advance our understanding of molecular mechanisms and signaling systems regulating pancreatic β cell fates.

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