Trans-2-enoyl-CoA reductase limits Ca(2+) accumulation in the endoplasmic reticulum by inhibiting the Ca(2+) pump SERCA2b

The endoplasmic reticulum (ER) contains various enzymes that metabolize fatty acids (FAs). Given that FAs are the components of membranes, FA metabolic enzymes might be associated with regulation of ER membrane functions. However, it remains unclear whether there is the interplay between FA metabolic enzymes and ER membrane proteins. Trans-2-enoyl-CoA reductase (TER) is an FA reductase present in the ER membrane and catalyzes the last step in the FA elongation cycle and sphingosine degradation pathway. Here we identify sarco(endo)plasmic reticulum Ca(2+)-ATPase 2b (SERCA2b), an ER Ca(2+) pump responsible for Ca(2+) accumulation in the ER, as a TER-binding protein by affinity purification from HEK293 cell lysates. We show that TER directly binds to SERCA2b by in vitro assays using recombinant proteins. Thapsigargin, a specific SERCA inhibitor, inhibits this binding. TER binds to SERCA2b through its conserved C-terminal region. TER overexpression suppresses SERCA2b ATPase activity in microsomal membranes of HEK293 cells. Depletion of TER increases Ca(2+) storage in the ER and accelerates SERCA2b-dependent Ca(2+) uptake to the ER after ligand-induced Ca(2+) release. Moreover, depletion of TER reduces the Ca(2+)-dependent nuclear translocation of nuclear factor of activated T cells 4. These results demonstrate that TER is a negative regulator of SERCA2b, implying the direct linkage of FA metabolism and Ca(2+) accumulation in the ER.