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Abstract
Secretory protein misfolding has been linked to ER stress and cell death. We expressed a TGrdw transgene encoding TG-G(2298)R, a misfolded mutant thyroglobulin reported to be linked to thyroid cell death. When the TGrdw transgene was expressed at low level in thyrocytes of TGcog/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.
Highlights
The thyroglobulin (TG) gene is the most highly expressed gene of the thyroid gland, and TG protein makes up more than 50% of all thyroidal protein
Transgenic animals were identified by tail vein PCR (Supplemental Figure 1C); the transgene was expressed at a low level (≤1% of endogenous TG mRNA in TGcog/cog mice) such that total TG mRNA in the thyroid of transgenic animals was unchanged from that in TGcog/cog mice (Supplemental Figure 2A), and both sets of 4-month-old animals had primary hypothyroidism
TGcog/cog animals exhibited dramatic ER stress as reported previously [13] — comparable ER stress was found in transgenic TGcog/cog mice as demonstrated by X-box binding protein-1 (XBP1) splicing (Figure 1A) with upregulation of ER chaperones, as well as CCAATenhancer-binding protein homologous protein (CHOP) (Figure 1B)
Summary
The thyroglobulin (TG) gene is the most highly expressed gene of the thyroid gland, and TG protein makes up more than 50% of all thyroidal protein. Misfolding of mutant TG in the ER is an established cause of congenital hypothyroidism [2], which, via endocrine feedback, triggers an increase in circulating levels of thyroid-stimulating hormone (TSH) released from the anterior pituitary In this disease (in both humans and animal models), thyroid follicular (thyrocyte) cell growth [3] and thyrocyte cell death [4] take place simultaneously in different cells of the same thyroid gland. This behavior suggests that affected cells in the same tissue exhibit a range of (successful and unsuccessful) attempts in adaptive response to chronic ER stress. Such a finding is consistent with the broader notion that a myriad of prosurvival and prodeath signals are generated as downstream consequences of ER stress [5], and there are likely to be both complex (and possibly subtle) changes in the profile and balance of these activities that trigger death in some cells while allowing survival and even proliferation of adjacent cells of the same cell type
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