DHHC21 is a STIM1 protein S-acyltransferase that modulates immune function in vivo.

Depletion of calcium from ER stores leads to the activation of calcium channels on the plasma membrane known as store-operated calcium entry. The proteins STIM1 and STIM2 function as ER calcium sensors, and upon store depletion, they undergo a conformational change that allows them to bind to and gate Orai calcium channels on the plasma membrane. We have shown that both Orai1 and STIM1 are dynamically S-acylated after store depletion, which is required for SOCE. These results suggest the requirement of a calcium-activated protein S-acyltransferase (PAT) such as DHHC21. Here, we show that DHHC21 is essential for SOCE in vitro and in vivo. Using the depilated mouse model that expresses DHHC21 but cannot be activated by calcium, we show that DHHC21 activation is a major mediator of STIM1 S-acylation and subsequent calcium entry. Plasma membrane-localized DHHC21 is dynamically recruited into Orai1/STIM1 puncta upon store depletion, where it physically binds to STIM1. Finally, we show that depilated mice phenocopy many aspects of autoimmune lymphoproliferative syndrome (ALPS), including defective Fas-mediated calcium release, T cell death, neutropenia, and increased serum vitamin B12 levels. Targeting DHHC21 may be therapeutically beneficial for ALPS and diseases associated with deregulated activation of STIM1, such as tubular aggregate myopathy and Stormorken syndrome.