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

Abstract

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 experience 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 ATF6with similar observations 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 maintain a disproportionately lower relative mRNA level of Cidea compared to 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 non-canonical ER stress-response program, with implications for cell death and survival.

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

“…Chronic, unremitting, and unresolved ER stress is a factor that can promote cell death ( 40 ); thus, the field of medicine is just beginning to attack ER stress–mediated cell death as a potential therapeutic approach to address various clinical disorders ( 41 , 42 ). However, from studies of hypothyroid patients and animal models bearing biallelic TG mutations ( 10 ) as well as cell culture models of the disease ( 43 ), we have been mostly impressed by continued thyrocyte proliferation ( 11 ) despite the ongoing stress-mediated thyrocyte cell death ( 21 ). In such a case, the entire thyroid gland overgrows, that is, beyond normal size ( 22 ).…”

Endoplasmic Reticulum Stress and Its Impact on Adipogenesis: Molecular Mechanisms Implicated

“…XBP1s induces the expression of various genes, such as FAS, SREBP1c, ACC, DGAT, ChREBP, PLIN, CIDE, ATGL, HSL, and others, as shown in Table 1 [47,86,[89][90][91]. This regulation allows XBP1s to exert a significant impact on physiological processes related to lipid metabolism and obesity.…”

Insights Into the Biogenesis and Emerging Functions of Lipid Droplets From Unbiased Molecular Profiling Approaches

“…The contribution of LD formation to ER stress adaptation might be contextual: while several studies describe the upregulation of UPR markers when neutral lipid synthesis and LD biogenesis are impaired ( Petschnigg et al, 2009 ; Chitraju et al, 2017 ; El Zowalaty et al, 2018 ), others suggest that lack of key LD formation regulators has little impact on ER homeostasis, at least under some conditions ( Nguyen et al, 2017 ). The levels of specific LD proteins such as PLIN2 or CIDE-A are responsive to ER stress; but again, their contribution appears to be contextual, and PLIN2 depletion can have opposite effects on ER homeostasis and ER stress sensitivity in different cell models ( Qiu et al, 2015 ; Chen et al, 2017 ; Morishita et al, 2021 ). Further, because several regulators of LD biogenesis are ER proteins, a standing question in the field is the dissection of effects due to loss of LDs, from those derived from altered ER architecture ( Roberts and Olzmann, 2020 ).…”