Abstract
Stress granules (SGs) in response to various stresses have been reported in many diseases. We previously reported the implication of programmed cell death 4 (Pdcd4) in obesity-induced stress responses, but the possible link between Pdcd4 and SGs remains lacking. In this study we showed that oxidized low-density lipoprotein (ox-LDL) or high-fat diet (HFD) induced SG formation in mouse macrophages and liver tissues, and Pdcd4 deficiency in mice remarkably reduced its formation. In response to ox-LDL, either endogenous or ectopic Pdcd4 displayed granule-like expression and co-localized with SG markers including T-cell-restricted intracellular antigen-1, fragile X mental retardation-related protein 1, and eukaryotic initiation factor 4A. Ectopic expression of truncated Pdcd4 that depleted specific RNA-binding motif significantly disrupted the SG formation, suggesting the direct involvement of Pdcd4 in ox-LDL-induced SGs through its RNA-binding activity. Additionally, Pdcd4 deficiency drove AKT activation and suppression of eIF2α phosphorylation, thereby contributing to the resistance to ox-LDL or HFD-induced SG formation. Collectively, our data suggest that Pdcd4 as a crucial regulator in SGs induced by ox-LDL or HFD maybe a potential target for mitigating SG-associated stress responses in obesity and related diseases.
Highlights
Stress granules (SGs) are translationally silent cytoplasmic ribonucleoprotein complexes that assemble during various types of cellular stresses such as heat shock, viral infection, oxidative and/or endoplasmic reticulum (ER) stresses [1,2,3]
Using T-cell-restricted intracellular antigen-1 (TIA-1) as a SG marker, we found that about 16.5% of WT macrophages isolated from high-fat diet (HFD)-fed mice displayed TIA-1 positive SGs, a significant increase when compared to macrophage isolated from ND-fed mice
Macrophages isolated from programmed cell death 4 (Pdcd4)-/mice on HFD did not display this increase, showing that Pdcd4 is required for SG formation under HFD (Fig 1A and 1B)
Summary
Stress granules (SGs) are translationally silent cytoplasmic ribonucleoprotein complexes that assemble during various types of cellular stresses such as heat shock, viral infection, oxidative and/or endoplasmic reticulum (ER) stresses [1,2,3]. In response to environmental emergency, cells can trigger a sudden translational arrest, leading to rapid polysome disassembly and subsequent assembly of heterogeneous mRNAs and translation factors[4]. Stress-induced phosphorylation of eIF2α is required for SG assembly in many stress responses through inhibiting cap-dependent translation initiation [1, 2]. AKT, known as protein kinase B, that regulates cell survival, growth, metabolism and stress [8, 9], has recently been reported to suppress eIF2α phosphorylation and contribute to relieved ER or oxidative stress [10]. The direct link between AKT and eIF2α during SG assembly remain unestablished
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
