A TMEM16J variant leads to dysregulated cytosolic calcium which may lead to renal disease

SIGIRR (single immunoglobulin IL‐1 related receptor), PKP3 (plakophilin 3), and TMEM16J (anoctamin 9), a putative calcium‐activated ion channel and phospholipid scramblase, control the immune response and the extent of inflammation. Variants of SIGIRR/PKP3/TMEM16J lead to severe inflammatory diseases such as pneumonia, enterocolitis, and kidney graft rejection. Meta‐analysis of genome‐wide association studies identified TMEM16J‐T604A as a promotor for chronic kidney disease (CKD), but the disease mechanism and function of TMEM16J remain unknown. Here, we demonstrate TMEM16J as a calcium‐activated calcium‐permeable channel, which is expressed in the endoplasmic reticulum (ER). TMEM16J controls the intracellular distribution of calcium, and inhibits intracellular receptor‐mediated Ca2+ signals and Ca2+‐dependent activation of ion channels, but augments transcription and release of pro‐inflammatory cytokines. Renal epithelial cells expressing the variant TMEM16J‐T604A show enhanced calcium signals when compared to cells expressing wt‐TMEM16J, and demonstrate spontaneous transcription and release of cytokines. This study identifies TMEM16J as an important regulator of intracellular Ca2+ signals, ion channel activity, and cytokine release. TMEM16J may therefore affect immune response in renal tissue and immune cells.