TY - JOUR
T1 - Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1
AU - Yang, Zhengfeng
AU - Yan, Hui
AU - Dai, Wentao
AU - Jing, Ji
AU - Yang, Yihu
AU - Mahajan, Sahil
AU - Zhou, Yubin
AU - Li, Weikai
AU - Macaubas, Claudia
AU - Mellins, Elizabeth D.
AU - Shih, Chien Cheng
AU - Fitzpatrick, James A.J.
AU - Faccio, Roberta
N1 - Funding Information:
We thank Deborah Veis for constructive discussions. This work was supported by NIH Grants R01 AR053628 and AR066551 (to R.F.), Shriners Hospital Grant 85100 (to R.F.), NIH Grants R01GM112003 and R21GM126532 (to Y.Z.), the Welch Foundation BE-1913 (to Y.Z.), the American Cancer Society RSG-16-215-01 TBE (to Y.Z.), National Key R&D Program of China 2018YFC0910500 (to W.D.), Shanghai Municipal Science and Technology Major Project 2017SHZDZX01 (to W.D.), National Natural Science Foundation of China 81672736 (to W.D.), Shanghai Municipal Commission of Science and Technology 14DZ2252000 (to W.D.), Shanghai Sailing Program 16YF1408600 (to W.D.). Calcium imaging was performed in the Hope Center and the Center for Investigation of Membrane Excitability Diseases (CIMED) Live Cell Imaging Facility at WUSM. Confocal and FRET imaging (Nikon A1Rsi) and analysis were performed through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children's Discovery Institute of Washington University and St. Louis Children's Hospital (CDI-CORE-2015-505) and the Foundation for Barnes-Jewish Hospital (3770).
Funding Information:
We thank Deborah Veis for constructive discussions. This work was supported by NIH Grants R01 AR053628 and AR066551 (to R.F.), Shriners Hospital Grant 85100 (to R.F.), NIH Grants R01GM112003 and R21GM126532 (to Y.Z.), the Welch Foundation BE-1913 (to Y.Z.), the American Cancer Society RSG-16-215-01 TBE (to Y.Z.), National Key R&D Program of China 2018YFC0910500 (to W.D.), Shanghai Municipal Science and Technology Major Project 2017SHZDZX01 (to W.D.), National Natural Science Foundation of China 81672736 (to W.D.), Shanghai Municipal Commission of Science and Technology 14DZ2252000 (to W.D.), Shanghai Sailing Program 16YF1408600 (to W.D.). Calcium imaging was performed in the Hope Center and the Center for Investigation of Membrane Excitability Diseases ( CIMED ) Live Cell Imaging Facility at WUSM. Confocal and FRET imaging (Nikon A1Rsi) and analysis were performed through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital ( CDI-CORE-2015-505 ) and the Foundation for Barnes-Jewish Hospital ( 3770 ).
Publisher Copyright:
© 2019
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - Macrophage activation
KW - Osteoclastogenesis
KW - SOCE
KW - STIM1
KW - Tmem178
UR - http://www.scopus.com/inward/record.url?scp=85064485228&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2019.04.015
DO - 10.1016/j.jaut.2019.04.015
M3 - Article
C2 - 31018906
AN - SCOPUS:85064485228
SN - 0896-8411
VL - 101
SP - 94
EP - 108
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
ER -