Enhancement of Ca2+release from store-operated Ca2+ entry by Coronavirus disease 2019 (COVID19) spike (S) protein.

Functions and viral infection mechanisms of coronavirus disease 2019 (COVID-19) have been recently investigated extensively, focusing on Spike (S) protein together with its receptor, ACE2. Although their relationships with COVID-19 are obvious, less attention has been paid to intracellular regulation of S protein-protein interaction. Here, we identified STIM1 (stromal interaction molecule 1 precursor) as a novel binding protein of S protein for the first time. Their association was further characterized. We found that S [ 1259 DD 1260 ] acidic motif specifically interacted with STIM1 C-terminal basic motif [ 671 RKKFPLKIFKKPLKK 685 ]. Both motifs were demonstrated to be essential for STIM1 and S protein interaction using immunoprecipitation and immunoblotting and confocal co-localization. We also elucidated that the association between the acidic tail motif of S protein and the C-terminal basic motif of STIM1 promoted Ca 2+ cytoplasmic release from the store-operated Ca 2+ ion entry (SOCE) by disrupting STIM1 function, suggesting that disrupting STIM1 function by S protein was one of its mode of actions for COVID-19 infection. For the first time, we demonstrated that S protein played a role as a Ca 2+ ion releasing enhancer for COVID-19 infection from SOCE through interrupting normal STIM1’s roles. Our findings may provide one of the new ways for curing or preventing COVID-19 pandemic recurrence.