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

Depletion of Ca2+ from ER stores leads to the activation of Ca2+ channels on the plasma membrane known as store-operated Ca2+ entry. The proteins STIM1 and STIM2 function as ER Ca2+ sensors, and upon store depletion, they undergo a conformational change that allows them to bind to and gate Orai Ca2+ 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 Ca2+-activated protein S-acyltransferase (PAT) such as DHHC21 (also known as zDHHC21). Here, we show that DHHC21 is essential for SOCE in vitro and in vivo. Using the depilated mouse model, which expresses DHHC21 that cannot be activated by Ca2+, we show that DHHC21 activation is a major mediator of STIM1 S-acylation and subsequent Ca2+ 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 Ca2+ release, T cell death, neutropenia and increased serum vitamin B12 levels. Targeting DHHC21 might be therapeutically beneficial for ALPS and diseases associated with deregulated activation of STIM1, such as tubular aggregate myopathy and Stormorken syndrome.