Endoplasmic Reticulum Stress, the Hypothalamus, and Energy Balance

Çakır, Işın; Nillni, Eduardo A.

doi:10.1016/j.tem.2019.01.002

Cited by 67 publications

(33 citation statements)

References 113 publications

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“…Indeed, a recent transcriptomic study identified that one of the main characteristics of the expression profile of corticotroph adenomas, per se, was overexpression of protein-targeting to the ER network [ 30 ]. Furthermore, it has been shown that unfolded/misfolded proteins accumulated due to the malfunctioning of the processing capacity in the ER leads to global translational repression in hypothalamic neurons and within the pituitary [ 31 , 32 ]. Our data suggest that SCA present a diminished ability for ER protein processing, and this may contribute to a decreased POMC gene and protein expression and therefore provide an explanation for their silence.…”

Section: Discussionmentioning

confidence: 99%

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Eieland

Normann

Sundaram

et al. 2020

Cancers

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Functioning (FCA) and silent corticotroph (SCA) pituitary adenomas act differently from a clinical perspective, despite both subtypes showing positive TBX19 (TPIT) and/or adrenocorticotropic hormone (ACTH) staining by immunohistochemistry. They are challenging to treat, the former due to functional ACTH production and consequently hypercortisolemia, and the latter due to invasive and recurrent behavior. Moreover, the molecular mechanisms behind their distinct behavior are not clear. We investigated global transcriptome and proteome changes in order to identify signaling pathways that can explain FCA and SCA differences (e.g., hormone production vs. aggressive growth). In the transcriptomic study, cluster analyses of differentially expressed genes revealed two distinct groups in accordance with clinical and histological classification. However, in the proteomic study, a greater degree of heterogeneity within the SCA group was found. Genes and proteins related to protein synthesis and vesicular transport were expressed by both adenoma groups, although different types and a distinct pattern of collagen/extracellular matrix proteins were presented by each group. Moreover, several genes related to endoplasmic reticulum protein processing were overexpressed in the FCA group. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph adenomas, namely, the increased protein processing capacity of FCA and a specific pattern of adhesion molecules that may play a role in the aggressiveness of SCA.

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Section: Discussionmentioning

confidence: 99%

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Eieland

Normann

Sundaram

et al. 2020

Cancers

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“…It is recently reported that the stress to the endoplasmic reticulum (ER) is closely related to the progression of skeletal disorders, including osteoporosis 6 . The ER stress is a general term with varying stress sources that impede the regular ER function 7 . Its evolutionarily conserved pathway leads to the unfolded protein response (UPR) 8 , in which protein kinase-like endoplasmic reticulum kinase (PERK) acts as a sensor for accumulation of unfolded proteins in the ER lumen of mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice

Liu

et al. 2019

Cell Death Dis

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Bone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and boneresorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticulum (ER) stress, which may activate autophagy. We hypothesized that eIF2α signaling regulates bone homeostasis by promoting autophagy in osteoblasts and inhibiting osteoclast development. To test the hypothesis, we employed salubrinal to elevate the phosphorylation of eIF2α in an ovariectomized (OVX) mouse model and cell cultures. In the OVX model, salubrinal prevented abnormal expansion of rough ER and decreased the number of acidic vesiculars. It regulated ER stressassociated signaling molecules such as Bip, p-eIF2α, ATF4 and CHOP, and promoted autophagy of osteoblasts via regulation of eIF2α, Atg7, LC3, and p62. Salubrinal markedly alleviated OVX-induced symptoms such as reduction of bone mineral density and bone volume fraction. In primary bone-marrow-derived cells, salubrinal increased the differentiation of osteoblasts, and decreased the formation of osteoclasts by inhibiting nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Live cell imaging and RNA interference demonstrated that suppression of osteoclastogenesis is in part mediated by Rac1 GTPase. Collectively, this study demonstrates that ER stress-autophagy axis plays an important role in OVX mice. Bone-forming osteoblasts are restored by maintaining phosphorylation of eIF2α, and bone-resorbing osteoclasts are regulated by inhibiting NFATc1 and Rac1 GTPase.

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“…The balance of the ER intraluminal concentrations of calcium depends on the energy requiring voltage-gated calcium channels [307]. Energy depletion or conditions leading to ineffective transport of calcium has an important role in protein folding and calcium homeostasis [308]. An increment in the cytoplasmic calcium concentration has been reported to increase oxidative damage [309].…”

Section: Conservation Of Autophagy Regulation In Yeast Modelsmentioning

confidence: 99%

Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

Dhakal

Macreadie

2020

IJMS

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Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD.

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Endoplasmic Reticulum Stress, the Hypothalamus, and Energy Balance

Cited by 67 publications

References 113 publications

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice

Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

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