Background: We noticed the presence of ACE2 acidic tail [799DD800] and STIM1 (Stromal Interaction Molecule 1 Precursor) C-terminal basic amino acid domain [671RKKFPLKIFKKPLKK685] by the protein amino acid sequence survey. Result: Association between ACE2 protein and STIM1 increases intracellular Ca+2 in the human cell, resulting in apoptosis and autophagy. Conclusion: Interaction between ACE2 protein and STIM1 is required for the infection of COVID-19. Significance: Association between ACE2 protein and STIM1 that promotes the intracellular Ca+2 for its infection through the host membrane fusion seems to be one of promising drug developing target points. The property and signaling mechanisms of the angiotensin produced by ACE2 (Angiotensin Converting Enzyme 2) have been well studied in the renin–angiotensin system. However, less attention has been attracted to the intracellular regulation of ACE2 protein. Using the information which [671RKKFPLKIFKKPLKK685] motif of STIM1 (Stromal Interaction Molecule 1 Precursor) is able to bind its partner proteins via two acidic amino acids (DD), we recognized that ACE2 contains the short acidic motif binding motif [799DD800] on its C-terminus. Moreover, we demonstrated that the protein interaction between STIM1 and ACE2 contributes to Ca2+ ion release from ER. We recognized that a novel mechanism of ACE2 regulation is modulated through interaction with STIM1, which binds directly to ACE2 as a COVID-19 receptor. Further, our findings provide clues why ACE2 helps to release cytoplasmic Ca+2 from store-operated Ca+2 entry to stimulate viral coat membrane fusion with host plasma membrane, after COVID-19 Spike protein binding to ACE2. Our finding also implicates that COVID-19 infection enhances cytoplasmic Ca+2 ion concentration by releasing Ca+2 ion from ER, through its S protein association with its host ACE2 and subsequent STIM1 activation. Thus, our findings may provide the novel target point to prevent COVID-19 pandemic recurring and cure it.