Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1
| Autor: | Ji Jing, Wentao Dai, Roberta Faccio, Elizabeth D. Mellins, James A. J. Fitzpatrick, Yihu Yang, Hui Yan, Yubin Zhou, Claudia Macaubas, Weikai Li, Sahil Mahajan, Chien-Cheng Shih, Zhengfeng Yang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
inorganic chemicals 0301 basic medicine medicine.medical_treatment Immunology Mutant Endoplasmic Reticulum Article Mice 03 medical and health sciences Intracellular Calcium-Sensing Proteins 0302 clinical medicine Osteogenesis medicine Animals Humans Immunology and Allergy Myeloid Cells Protein Interaction Domains and Motifs Stromal Interaction Molecule 1 030203 arthritis & rheumatology Chemistry ORAI1 Macrophages Endoplasmic reticulum Mutagenesis Membrane Proteins STIM1 Macrophage Activation Store-operated calcium entry Transmembrane protein Neoplasm Proteins Cell biology HEK293 Cells 030104 developmental biology Cytokine Gene Expression Regulation Calcium Female Protein Binding |
| Zdroj: | Journal of Autoimmunity. 101:94-108 |
| ISSN: | 0896-8411 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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