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Inhibition of x-box binding protein 1 reduces tunicamycin-induced apoptosis in aged murine macrophages.

ABSTRACT: Endoplasmic reticulum (ER) stress is induced by the accumulation of unfolded and misfolded proteins in the ER. Although apoptosis induced by ER stress has been implicated in several aging-associated diseases, such as atherosclerosis, it is unclear how aging modifies ER stress response in macrophages. To decipher this relationship, we assessed apoptosis in macrophages isolated from young (1.5-2 months) and aged (16-18 months) mice and exposed the cells to the ER stress inducer tunicamycin. We found that aged macrophages exhibited more apoptosis than young macrophages, which was accompanied by reduced activation of phosphorylated inositol-requiring enzyme-1 (p-IRE1?), one of the three key ER stress signal transducers. Reduced gene expression of x-box binding protein 1 (XBP1), a downstream effector of IRE1?, enhanced p-IRE1? levels and reduced apoptosis in aged, but not young macrophages treated with tunicamycin. These findings delineate a novel, age-dependent interaction by which macrophages undergo apoptosis upon ER stress, and suggest an important protective role of IRE1? in aging-associated ER stress-induced apoptosis. This novel pathway may not only be important in our understanding of longevity, but may also have important implications for pathogenesis and potential treatment of aging-associated diseases in general.

SUBMITTER: Song Y

PROVIDER: S-EPMC3773058 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Inhibition of x-box binding protein 1 reduces tunicamycin-induced apoptosis in aged murine macrophages.

Song Yang Y Shen Hua H Du Wei W Goldstein Daniel R DR

Aging cell 20130707 5

Endoplasmic reticulum (ER) stress is induced by the accumulation of unfolded and misfolded proteins in the ER. Although apoptosis induced by ER stress has been implicated in several aging-associated diseases, such as atherosclerosis, it is unclear how aging modifies ER stress response in macrophages. To decipher this relationship, we assessed apoptosis in macrophages isolated from young (1.5-2 months) and aged (16-18 months) mice and exposed the cells to the ER stress inducer tunicamycin. We fou ...[more]

PMID: 23711292

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Project description:Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.

Dataset Information

Inhibition of x-box binding protein 1 reduces tunicamycin-induced apoptosis in aged murine macrophages.

Publications

Inhibition of x-box binding protein 1 reduces tunicamycin-induced apoptosis in aged murine macrophages.

Similar Datasets

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