Cell death–associated lipid droplet protein CIDE-A is a noncanonical marker of endoplasmic reticulum stress

Secretory protein misfolding has been linked to ER stress and cell death. We expressed a TG(rdw) transgene encoding TG-G(2298)R, a misfolded mutant thyroglobulin reported to be linked to thyroid cell death. When the TG(rdw) transgene was expressed at low level in thyrocytes of TG(cog/cog) mice that experienced severe ER stress, we observed increased thyrocyte cell death and increased expression of CIDE-A (cell death-inducing DFFA-like effector-A, a protein of lipid droplets) in whole thyroid gland. Here we demonstrate that acute ER stress in cultured PCCL3 thyrocytes increases Cidea mRNA levels, maintained at least in part by increased mRNA stability, while being negatively regulated by activating transcription factor 6 — with similar observations that ER stress increases Cidea mRNA levels in other cell types. CIDE-A protein is sensitive to proteasomal degradation yet is stabilized by ER stress, and elevated expression levels accompany increased cell death. Unlike acute ER stress, PCCL3 cells adapted and surviving chronic ER stress maintained a disproportionately lower relative mRNA level of Cidea compared with that of other, classical ER stress markers, as well as a blunted Cidea mRNA response to a new, unrelated acute ER stress challenge. We suggest that CIDE-A is a novel marker linked to a noncanonical ER stress response program, with implications for cell death and survival.