Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia

Nakashima, Akitoshi; Cheng, Shi Bin; Ikawa, Masahito; Yoshimori, Tamotsu; Huber, Warren J.; Menon, Ramkumar; Huang, Zheping; Fierce, Jamie; Padbury, Jamés F.; Sadovsky, Yoel; Saito, Shigeru; Sharma, Surendra

doi:10.1080/15548627.2019.1707494

Cited by 86 publications

(124 citation statements)

References 68 publications

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“…Studies in this murine model have revealed the accumulation of p62, an autophagy inhibition marker in the mouse placentas and human preeclamptic placentas. 35 The spongiotrophoblast layer is smaller in the Atg7 knockout placentas when compared with those of the wildtype placentas, suggesting that the spongiotrophoblast layer is more susceptible to autophagy deficiency in murine placentas. The absence of Atg7 also increases cell death due to DNA damage under starvation conditions in vitro.…”

Section: Role Of Autophagy In In Vivo Embryogenesis and Placentationmentioning

confidence: 94%

“…Misfolded proteins from the serum of a patient with preeclampsia form larger aggregates in the autophagy-deficient cells and can be detected. 35 TFEB inhibition in the clinical setting could be attributed to chronic hypoxia, a wellknown stressor seen in the placentas of women suffering from preeclampsia. Chronic hypoxia decreases the expression level of TFEB, impairs autolysosome formation and induces hyperactivation of mTOR, leading to the inhibition of nuclear translocation of TFEB in trophoblast cells.…”

Section: Role Of Autophagy In Placentation During Mid-gestation Periomentioning

confidence: 99%

“…2). 35 Loss of TFEB in the placentas is associated with a reduction of vascular endothelial growth factor (VEGF) and results in embryonic lethality due to undeveloped vascularization in the labyrinth layer 46 . Nuclear translocation of TFEB, a maker of TFEB activation, is completely defected in the autophagy‐deficient cells in response to the lysosomal inhibitor, bafilomycin A1, indicating hyperactivation of the mammalian target of rapamycin (mTOR) as an inhibitory mechanism of autophagy.…”

Section: Role Of Autophagy In Placentation During Mid‐gestation Periodmentioning

confidence: 99%

“…Nuclear translocation of TFEB, a maker of TFEB activation, is completely defected in the autophagy‐deficient cells in response to the lysosomal inhibitor, bafilomycin A1, indicating hyperactivation of the mammalian target of rapamycin (mTOR) as an inhibitory mechanism of autophagy. Misfolded proteins from the serum of a patient with preeclampsia form larger aggregates in the autophagy‐deficient cells and can be detected 35 . TFEB inhibition in the clinical setting could be attributed to chronic hypoxia, a well‐known stressor seen in the placentas of women suffering from preeclampsia.…”

Section: Role Of Autophagy In Placentation During Mid‐gestation Periodmentioning

confidence: 99%

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Placental autophagy failure: A risk factor for preeclampsia

Nakashima

Saito

Aoki

et al. 2020

J of Obstet and Gynaecol

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Hypertensive disorders of pregnancy, including preeclampsia, directly affect maternal and perinatal morbidity and mortality. As the pathophysiology of preeclampsia is multi-factorial and has been studied using different approaches, we have demonstrated that impaired autophagy is an intertwined risk factor for preeclampsia. This concept has been verified in both in vitro and in vivo experiments. Autophagy is primarily involved in maintaining cellular homeostasis, and in immune regulation, longevity, cytokines secretion and a variety of other biological functions. Here, we review the role of autophagy in normal embryogenesis and placentation. Once placental autophagy is impaired by metabolic stress such as hypoxia, endoplasmic reticulum stress or starvation, placental development could be disrupted, resulting in functional maladaptations at the maternal-fetal interface. These malfunctions may result in fetal growth restriction or preeclampsia.

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Section: Role Of Autophagy In In Vivo Embryogenesis and Placentationmentioning

confidence: 94%

Section: Role Of Autophagy In Placentation During Mid-gestation Periomentioning

confidence: 99%

Section: Role Of Autophagy In Placentation During Mid‐gestation Periodmentioning

confidence: 99%

Section: Role Of Autophagy In Placentation During Mid‐gestation Periodmentioning

confidence: 99%

See 2 more Smart Citations

Placental autophagy failure: A risk factor for preeclampsia

Nakashima

Saito

Aoki

et al. 2020

J of Obstet and Gynaecol

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show abstract

“…Aggregated, misfolded proteins have been detected in serum and urine of pre‐eclampsia patients 72‐74 and have been shown to induce pre‐eclampsia‐like features in pregnant mice 72 . We have attributed this excess protein aggregation in pre‐eclampsia to compromised autophagy in trophoblasts, which in turn contributes to poor placentation and hypertension 75,76 . Autophagy is a degradation system present in cells that maintains cellular homeostasis by eliminating misfolded or aggregated proteins 77 .…”

Section: Placental Evs and Pre‐eclampsiamentioning

confidence: 99%

Placental extracellular vesicles and pre‐eclampsia

Schuster

Cheng

Padbury

et al. 2020

American J Rep Immunol

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Pre‐eclampsia is a hypertensive disease of pregnancy characterized by new‐onset hypertension, with either proteinuria and/or organ dysfunction. Pre‐eclampsia is a leading cause of maternal morbidity and mortality; however, the underlying cellular and molecular mechanisms are not well understood. There is consensus that the underlying mechanism(s) resulting in pre‐eclampsia is centered around abnormal placentation, inadequate spiral‐artery remodeling, and deficiency in trophoblast invasion, resulting in impaired maternal blood flow to the placenta and a release of signals and/or inflammatory mediators into maternal circulation triggering the systemic manifestations of pre‐eclampsia. ER stress, resulting in impaired autophagy and placental release of aggregated proteins, may also confer systemic stress to maternal organs in pre‐eclampsia. Extracellular vesicles (EVs), lipid‐bilayer enclosed structures containing macromolecules including proteins, miRNA, and other important nucleotides, have been suggested to play an important role in this maternal‐fetal communication. Circulating EVs are present in greater quantity in the plasma of pre‐eclampsia subjects compared to normal pregnancy, and the placental derived EVs have been shown to have altered protein and RNA cargo. In this review, we will focus on EVs and their role in pre‐eclampsia, specifically their role in immune responses, inflammation, altered angiogenesis, and endothelial dysfunction.

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HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress‐driven hepatocellular carcinoma progression

et al. 2023

Cancer Communications

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BackgroundThe mechanism of hepatitis B virus (HBV)‐induced carcinogenesis remains an area of interest. The accumulation of hepatitis B surface antigen in the endoplasmic reticulum (ER) of hepatocytes stimulates persistent ER stress. Activity of the unfolded protein response (UPR) pathway of ER stress may play an important role in inflammatory cancer transformation. How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV‐related hepatocellular carcinoma (HCC) is still unclear. Here, we aimed to define the key molecule hyaluronan‐mediated motility receptor (HMMR) in this process and explore its role under ER stress in HCC development.MethodsAn HBV‐transgenic mouse model was used to characterize the pathological changes during the tumor progression. Proteomics and transcriptomics analyses were performed to identify the potential key molecule, screen the E3 ligase, and define the activation pathway. Quantitative real‐time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines. Luciferase reporter assay, chromatin immunoprecipitation, coimmunoprecipitation, immunoprecipitation, and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress. Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues.ResultsWe found sustained activation of ER stress in the HBV‐transgenic mouse model of hepatitis‐fibrosis‐HCC. HMMR was transcribed by c/EBP homologous protein (CHOP) and degraded by tripartite motif containing 29 (TRIM29) after ubiquitination under ER stress, which caused the inconsistent expression of mRNA and protein. Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR. HMMR could alleviate ER stress by increasing autophagic lysosome activity. The negative correlation between HMMR and ER stress, positive correlation between HMMR and autophagy, and negative correlation between ER stress and autophagy were verified in human tissues.ConclusionsThis study identified the complicated role of HMMR in autophagy and ER stress, that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression, which could be a novel explanation for HBV‐related carcinogenesis.

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Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia

Cited by 86 publications

References 68 publications

Placental autophagy failure: A risk factor for preeclampsia

Placental autophagy failure: A risk factor for preeclampsia

Placental extracellular vesicles and pre‐eclampsia

HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress‐driven hepatocellular carcinoma progression

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