Abstract
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 RTN4, is sufficient to alter ER morphology and severely compromise SOCE. Mechanistically, we show this to be the result of defective STIM1-Orai1 coupling because of loss of ER tubulation and redistribution of STIM1 to ER sheets. As a functional consequence, RTN4-depleted cells fail to sustain elevated cytoplasmic Ca(2+) levels via SOCE and therefor are less susceptible to Ca(2+) overload induced apoptosis. Thus, for the first time, our results show a direct correlation between ER morphology and SOCE and highlight the importance of RTN4 in cellular Ca(2+) homeostasis.
Highlights
Store-operated calcium entry requires the redistribution of endoplasmic reticulum (ER) localized STIM1 to ER-plasma membrane (PM) junctions
MEFs abundantly express the ϳ45 kDa RTN4b protein (Fig. 1A) with very little RTN4a. This is consistent with non-neural cells such as endothelial, smooth muscle, and macrophages expressing higher levels of RTN4b compared with RTN4a [20, 36]
Because STIM1 and subsequent Orai1 clustering become apparent only upon reaching ER-PM junctions and coupling to one another, respectively, these results suggest of defective targeted diffusion of endogenous STIM1 following internal Ca2ϩ stores depletion in RTN4-KO MEFs
Summary
Store-operated calcium entry requires the redistribution of ER localized STIM1 to ER-PM junctions. We show that the loss of RTN4, is sufficient to alter ER morphology and severely compromise SOCE We show this to be the result of defective STIM1-Orai coupling because of loss of ER tubulation and redistribution of STIM1 to ER sheets. ER sheets are relatively flat structures that are densely packed with polyribosomes, offer a large volume-to-surface ratio, and are enriched in proteins involved in the synthesis, folding, and sorting of integral membrane and secreted proteins [3]. These structures are abundant in professional secretory cells, such as plasma cells and pancreatic cells.
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