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Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1.


ABSTRACT: Store-operated calcium entry (SOCE) modulates cytosolic calcium in multiple cells. Endoplasmic reticulum (ER)-localized STIM1 and plasma membrane (PM)-localized ORAI1 are two main components of SOCE. STIM1:ORAI1 association requires STIM1 oligomerization, its re-distribution to ER-PM junctions, and puncta formation. However, little is known about the negative regulation of these steps to prevent calcium overload. Here, we identified Tmem178 as a negative modulator of STIM1 puncta formation in myeloid cells. Using site-directed mutagenesis, co-immunoprecipitation assays and FRET imaging, we determined that Tmem178:STIM1 association occurs via their transmembrane motifs. Mutants that increase Tmem178:STIM1 association reduce STIM1 puncta formation, SOCE activation, impair inflammatory cytokine production in macrophages and osteoclastogenesis. Mutants that reduce Tmem178:STIM1 association reverse these effects. Furthermore, exposure to plasma from arthritic patients decreases Tmem178 expression, enhances SOCE activation and cytoplasmic calcium. In conclusion, Tmem178 modulates the rate-limiting step of STIM1 puncta formation and therefore controls SOCE in inflammatory conditions.

SUBMITTER: Yang Z 

PROVIDER: S-EPMC7102427 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1.

Yang Zhengfeng Z   Yan Hui H   Dai Wentao W   Jing Ji J   Yang Yihu Y   Mahajan Sahil S   Zhou Yubin Y   Li Weikai W   Macaubas Claudia C   Mellins Elizabeth D ED   Shih Chien-Cheng CC   Fitzpatrick James A J JAJ   Faccio Roberta R  

Journal of autoimmunity 20190422


Store-operated calcium entry (SOCE) modulates cytosolic calcium in multiple cells. Endoplasmic reticulum (ER)-localized STIM1 and plasma membrane (PM)-localized ORAI1 are two main components of SOCE. STIM1:ORAI1 association requires STIM1 oligomerization, its re-distribution to ER-PM junctions, and puncta formation. However, little is known about the negative regulation of these steps to prevent calcium overload. Here, we identified Tmem178 as a negative modulator of STIM1 puncta formation in my  ...[more]

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