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Trans-2-enoyl-CoA reductase limits Ca²⁺ accumulation in the endoplasmic reticulum by inhibiting the Ca²⁺ pump SERCA2b.

ABSTRACT: 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 Ca²⁺-ATPase 2b (SERCA2b), an ER Ca²⁺ pump responsible for Ca²⁺ 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 Ca²⁺ storage in the ER and accelerates SERCA2b-dependent Ca²⁺ uptake to the ER after ligand-induced Ca²⁺ release. Moreover, depletion of TER reduces the Ca²⁺-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 Ca²⁺ accumulation in the ER.

SUBMITTER: Uchida Y

PROVIDER: S-EPMC7949109 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Trans-2-enoyl-CoA reductase limits Ca2+ accumulation in the endoplasmic reticulum by inhibiting SERCA2b Ca2+ pump

Project description:The endoplasmic reticulum (ER) contains various enzymes that metabolize fatty acids (FAs). How FA metabolic enzymes cooperate with other ER functions, such as calcium (Ca2+) accumulation and its regulated release to the cytosol, is elusive. Trans-2-enoyl-CoA reductase (TER) is a FA reductase present in the ER membrane, and catalyzes the last step of FA elongation cycle and sphingosine degradation pathway. Here we show that TER directly binds to an ER Ca2+ pump, sarco(endo)plasmic reticulum Ca2+-ATPase 2b (SERCA2b), and regulates its activity. 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. Depletion of TER increases the ER Ca2+ storage and accelerates SERCA2b-dependent Ca2+ uptake to the ER after ligand-induced Ca2+ release. These results demonstrate that TER is a negative regulator of SERCA2b, implying the direct linkage of FA metabolism and Ca2+ accumulation in the ER.

2021-01-13 | PXD020792 | Pride

A Novel Cytosolic Isoform of Mitochondrial Trans-2-Enoyl-CoA Reductase Enhances Peroxisome Proliferator-Activated Receptor ? Activity.

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Characterization of two cotton cDNAs encoding trans-2-enoyl-CoA reductase reveals a putative novel NADPH-binding motif.

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Observed crowding effects on Mycobacterium tuberculosis 2-trans-enoyl-ACP (CoA) reductase enzyme activity are not due to excluded volume only.

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