| First Author | Schreiber R | Year | 2023 |
| Journal | FASEB J | Volume | 37 |
| Issue | 1 | Pages | e22683 |
| PubMed ID | 36520003 | Mgi Jnum | J:352392 |
| Mgi Id | MGI:7434871 | Doi | 10.1096/fj.202200968R |
| Citation | Schreiber R, et al. (2023) A TMEM16J variant leads to dysregulated cytosolic calcium which may lead to renal disease. FASEB J 37(1):e22683 |
| abstractText | 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 Ca(2+) signals and Ca(2+) -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 Ca(2+) signals, ion channel activity, and cytokine release. TMEM16J may therefore affect immune response in renal tissue and immune cells. |
