Reticluon 4 is necessary for ER tubulation, STIM1-Orai1 coupling and store-operated calcium entry [Cell Biology]

March 11th, 2014 by Jozsef, L., Tashiro, K., Kuo, A., Park, E. J., Skoura, A., Albinsson, S., Rivera-Molina, F., Harrison, K. D., Iwakiri, Y., Toomre, D., Sessa, W. C.

Despite recent advances in understanding store-operated calcium entry (SOCE) regulation, the fundamental question of how ER morphology affects this process remains unanswered. Here we show that the loss of a single isoform of RTN4, RTN4b, is sufficient to alter ER morphology and severely compromise SOCE. Mechanistically, we show this to be the result of defective STIM1-Orai1 coupling due to loss of ER tubulation and redistribution of STIM1 to ER sheets. As a functional consequence, RTN4b depleted cells fail to sustain elevated cytoplasmic Ca2+ levels via SOCE and therefor are less susceptible to Ca2+ overload induced apoptosis. Thus, for the first time, our results show a direct correlation between ER morphology and SOCE and highlight the importance of RTN4b in cellular Ca2+ homeostasis.