TPC2-mediated lysosomal Ca²⁺ release puts the brakes on store-operated Ca²⁺ entry

Lysosomal Ca²⁺ release can trigger endoplasmic reticulum (ER) Ca²⁺ mobilisation, which would be expected to activate store-operated Ca²⁺ entry (SOCE). Recent work by Lee et al. reveals that activation of the lysosomal two-pore channel TPC2 instead suppresses SOCE despite ER Ca²⁺ depletion. TPC2-derived Ca²⁺ signals recruit calmodulin to promote STIM1 inactivation, imparing STIM oligomerisation and coupling to Orai1. These findings identify a lysosomal feedback pathway that restrains Ca²⁺ influx and expand the role of TPC2 from an initiator of intracellular Ca²⁺ release to a brake on SOCE.