Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress

Dang, Thao Thi Phuong; Kim, Mi-Jeong; Lee, Yoon Young; Le, Hien Thi Thu; Kim, Kook Hwan; Nam, Somi; Hyun, Seung Hwa; Kim, Hong Lim; Chung, Sung Min; Chung, Hun Taeg; Jho, Eek-hoon; Yoshida, Hiderou; Kim, Kyoungmi; Park, Chan Young; Lee, Myung-Shik; Back, Sung Hoon

doi:10.1080/15548627.2023.2173900

Cited by 14 publications

(4 citation statements)

References 107 publications

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“…Moreover, it has been suggested that muscle atrophy could be alleviated by targeting the p97-NPLOC4 complex [26]. The identification of EIF2S1/eIF2α phosphorylation as a crucial mechanism helps regulate pathways for unfolded proteins and uphold intracellular homeostasis [27]. MDA-T68 cells showed significant upregulation of DERL1 in both thyroid cancer tissues and cell lines.…”

Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed ER stress-related genes and their association with pulmonary arterial hypertension

Yang,

Lai,

Xie

et al. 2024

Respir Res

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Background Pulmonary arterial hypertension (PAH) is a complex and progressive illness that has a multifaceted origin, significant fatality rates, and profound effects on health. The pathogenesis of PAH is poorly defined due to the insufficient understanding of the combined impact of endoplasmic reticulum (ER) stress and immune infiltration, both of which play vital roles in PAH development. This study aims to identify potential ER stress-related biomarkers in PAH and investigate their involvement in immune infiltration. Methods The GEO database was used to download gene expression profiles. Genes associated with ER stress were obtained from the MSigDB database. Weighted gene co-expression network analysis (WGCNA), GO, KEGG, and protein-protein interaction (PPI) were utilized to conduct screening of hub genes and explore potential molecular mechanisms. Furthermore, the investigation also delved into the presence of immune cells in PAH tissues and the correlation between hub genes and the immune system. Finally, we validated the diagnostic value and expression levels of the hub genes in PAH using subject-workup characterization curves and real-time quantitative PCR. Results In the PAH and control groups, a total of 31 genes related to ER stress were found to be differentially expressed. The enrichment analysis revealed that these genes were primarily enriched in reacting to stress in the endoplasmic reticulum, dealing with unfolded proteins, transporting proteins, and processing proteins within the endoplasmic reticulum. EIF2S1, NPLOC4, SEC61B, SYVN1, and DERL1 were identified as the top 5 hub genes in the PPI network. Immune infiltration analysis revealed that these hub genes were closely related to immune cells. The receiver operating characteristic (ROC) curves revealed that the hub genes exhibited excellent diagnostic efficacy for PAH. The levels of SEC61B, NPLOC4, and EIF2S1 expression were in agreement with the findings of bioinformatics analysis in the PAH group. Conclusions Potential biomarkers that could be utilized are SEC61B, NPLOC4, and EIF2S1, as identified in this study. The infiltration of immune cells was crucial to the development and advancement of PAH. This study provided new potential therapeutic targets for PAH.

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Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed ER stress-related genes and their association with pulmonary arterial hypertension

Yang,

Lai,

Xie

et al. 2024

Respir Res

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“…TFEB was recently discovered as a major regulator of the ALP as well as a potential therapeutic target [ 35 ]. In addition, PPP3CB-mediated dephosphorylation of TFEB, and YWHA/14-3-3 dissociation were required for TFEB nuclear translocation [ 36 ]. In the present study, total TFEB expression was increased in response to MDP treatment.…”

Section: Discussionmentioning

confidence: 99%

Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries

Fang,

Jing,

Zhang

et al. 2023

J Transl Med

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Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391–964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1–247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway.

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“…Additionally, the deletion of SEC61B induced ER stress in mammalian cells and Caenorhabditis elegans [22], and targeting the p97-NPLOC4 complex may be a strategy to combat muscle atrophy [23]. Phosphorylation of EIF2S1/eIF2α was identi ed as an important mechanism to regulate unfolded protein pathways and maintain intracellular homeostasis [24]. DERL1 exhibited a signi cant upregulation in both thyroid cancer tissues and cell lines, and the overexpression of miR-575 led to the inhibition of DERL1 in MDA-T68 cells [25].…”

Section: Discussionmentioning

confidence: 99%

Identification of Differentially Expressed ER Stress-Related Genes and Their Association with Pulmonary Arterial Hypertension

Yang,

Lai,

Xie

et al. 2023

Preprint

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Pulmonary arterial hypertension (PAH) is a progressive disease with a complex etiology, a high mortality rate, and strong harm. Endoplasmic reticulum (ER) stress and immune infiltration are key to the pathogenesis of PAH, but their interaction in PAH is still unclear. In this study, we investigated the role of ER stress and immune infiltration in PAH and their interrelationships using bioinformatics methods. Gene expression profiles and ER stress-related genes were downloaded from the Gene Expression Omnibus (GEO) and MSigDB databases, respectively. A total of 31 differentially expressed ER stress-related genes highly associated with PAH were identified by the Limma software package and weighted gene co-expression network analysis (WGCNA). Enrichment analysis showed that these genes were mainly enriched in response to endoplasmic reticulum stress, response to unfolded proteins, protein transport, and protein processing in the endoplasmic reticulum. Subsequently, the identification of the top five hub genes (EIF2S1, NPLOC4, SEC61B, SYVN1, and DERL1) was accomplished through screening within the protein-protein interaction (PPI) network. Immune infiltration analysis showed that these hub genes were closely related to immune cells. The receiver operating characteristic (ROC) curves showed that hub genes had a good diagnostic value for PAH. Ultimately, a rat model of pulmonary arterial hypertension (PAH) was successfully established, wherein the observed expression levels of SEC61B, NPLOC4, and EIF2S1 in the PAH group aligned with the outcomes derived from bioinformatics analysis. The SEC61B, NPLOC4, and EIF2S1 identified in this study could be used as potential biomarkers. This study provided new potential therapeutic targets for the prevention and treatment of PAH.

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Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress

Cited by 14 publications

References 107 publications

Identification of differentially expressed ER stress-related genes and their association with pulmonary arterial hypertension

Identification of differentially expressed ER stress-related genes and their association with pulmonary arterial hypertension

Erbin accelerates TFEB-mediated lysosome biogenesis and autophagy and alleviates sepsis-induced inflammatory responses and organ injuries

Identification of Differentially Expressed ER Stress-Related Genes and Their Association with Pulmonary Arterial Hypertension

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