Endoplasmic Reticulum Dysfunction in Brain Pathology: Critical Role of Protein Synthesis

The endoplasmic reticulum (ER) comprises morphologically and functionally distinct domains: sheets and interconnected tubules. These domains undergo dynamic reshaping in response to changes in the cellular environment. However, the mechanisms behind this rapid remodeling are largely unknown. Here, we report that ER remodeling is actively driven by lysosomes, following lysosome repositioning in response to changes in nutritional status: The anchorage of lysosomes to ER growth tips is critical for ER tubule elongation and connection. We validate this causal link via the chemo- and optogenetically driven repositioning of lysosomes, which leads to both a redistribution of the ER tubules and a change of its global morphology. Therefore, lysosomes sense metabolic change in the cell and regulate ER tubule distribution accordingly. Dysfunction in this mechanism during axonal extension may lead to axonal growth defects. Our results demonstrate a critical role of lysosome-regulated ER dynamics and reshaping in nutrient responses and neuronal development.

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SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum

Journal of Virology ◽

10.1128/jvi.00232-17 ◽

2017 ◽

Vol 91 (12) ◽

Cited By ~ 16

Author(s):

Allison Dupzyk ◽

Jeffrey M. Williams ◽

Parikshit Bagchi ◽

Takamasa Inoue ◽

Billy Tsai

Keyword(s):

Endoplasmic Reticulum ◽

Biological Membrane ◽

Critical Role ◽

Simian Virus 40 ◽

Simian Virus ◽

Membrane Penetration ◽

Critical Function ◽

Nonenveloped Virus ◽

Er Membrane

ABSTRACT Membrane penetration by nonenveloped viruses remains enigmatic. In the case of the nonenveloped polyomavirus simian virus 40 (SV40), the virus penetrates the endoplasmic reticulum (ER) membrane to reach the cytosol and then traffics to the nucleus to cause infection. We previously demonstrated that the cytosolic Hsc70-SGTA-Hsp105 complex is tethered to the ER membrane, where Hsp105 and SGTA facilitate the extraction of SV40 from the ER and transport of the virus into the cytosol. We now find that Hsc70 also ejects SV40 from the ER into the cytosol in a step regulated by SGTA. Although SGTA's N-terminal domain, which mediates homodimerization and recruits cellular adaptors, is dispensable during ER-to-cytosol transport of SV40, this domain appears to exert an unexpected post-ER membrane translocation function during SV40 entry. Our study thus establishes a critical function of Hsc70 within the Hsc70-SGTA-Hsp105 complex in promoting SV40 ER-to-cytosol membrane penetration and unveils a role of SGTA in controlling this step. IMPORTANCE How a nonenveloped virus transports across a biological membrane to cause infection remains mysterious. One enigmatic step is whether host cytosolic components are co-opted to transport the viral particle into the cytosol. During ER-to-cytosol membrane transport of the nonenveloped polyomavirus SV40, a decisive infection step, a cytosolic complex composed of Hsc70-SGTA-Hsp105 was previously shown to associate with the ER membrane. SGTA and Hsp105 have been shown to extract SV40 from the ER and transport the virus into the cytosol. We demonstrate here a critical role of Hsc70 in SV40 ER-to-cytosol penetration and reveal how SGTA controls Hsc70 to impact this process.

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Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1

Biochemistry ◽

10.1021/acs.biochem.6b01170 ◽

2017 ◽

Vol 56 (10) ◽

pp. 1546-1558 ◽

Cited By ~ 19

Author(s):

Athanasios Stamogiannos ◽

Zachary Maben ◽

Athanasios Papakyriakou ◽

Anastasia Mpakali ◽

Paraskevi Kokkala ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Conformational Change ◽

Catalytic Mechanism ◽

Critical Role ◽

Endoplasmic Reticulum Aminopeptidase 1 ◽

Interdomain Interactions

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Inhibition of Endoplasmic Reticulum Stress Reverses Synaptic Plasticity Deficits in Striatum of DYT1 Dystonia Mice

10.21203/rs.3.rs-166434/v1 ◽

2021 ◽

Author(s):

Huaying Cai ◽

Linhui Ni ◽

Xingyue Hu ◽

Xianjun Ding

Keyword(s):

Endoplasmic Reticulum ◽

Synaptic Plasticity ◽

Er Stress ◽

Critical Role ◽

Stress Protein ◽

Long Term Potentiation ◽

Research Field ◽

Protein Levels ◽

Dyt1 Dystonia

Abstract Background & objectiveStriatal plasticity alterations caused by endoplasmic reticulum (ER) stress is supposed to be critically involved in the mechanism of DYT1 dystonia. In the current study, we expanded this research field by investigating the critical role of ER stress underlying synaptic plasticity impairment imposed by mutant heterozygous Tor1a+/- in a DYT1 dystonia mouse model.Methods & resultsLong-term depression (LTD) was failed to be induced, while long-term potentiation (LTP) was further strengthened in striatal spiny neurons (SPNs) from the Tor1a+/- DYT1 dystonia mice. Spine morphology analyses revealed a significant increase of both number of mushroom type spines and spine width in Tor1a+/- SPNs. In addition, increased AMPA receptor function and the reduction of NMDA/AMPA ratio in the postsynaptic of Tor1a+/- SPNs was observed, along with increased ER stress protein levels in Tor1a+/- striatum. Notably, ER stress inhibitors, tauroursodeoxycholic acid (TUDCA), could rescue LTD as well as AMPA currents.ConclusionThe current study illustrated the role of ER stress in mediating structural and functional plasticity alterations in Tor1a+/- SPNs. Inhibition of the ER stress by TUDCA is beneficial in reversing the deficits at the cellular and molecular levels. Remedy of dystonia associated neurological and motor functional impairment by ER stress inhibitors could be a recommendable therapeutic agent in clinical practice.

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Synthesis of eosinophil-associated enzymes in HL-60 promyelocytic leukemia cells

Blood ◽

10.1182/blood.v68.1.185.185 ◽

1986 ◽

Vol 68 (1) ◽

pp. 185-192 ◽

Cited By ~ 14

Author(s):

SA Fischkoff ◽

GE Brown ◽

A Pollak

Keyword(s):

Endoplasmic Reticulum ◽

Protein Synthesis ◽

Promyelocytic Leukemia ◽

Leukemia Cells ◽

Acute Myelomonocytic Leukemia ◽

Granule Morphology ◽

Synthesis And Processing ◽

Low Levels ◽

Myelomonocytic Leukemia

Abstract Eosinophils derived from HL-60 cells share many of the abnormalities of granule histochemistry and morphology frequently seen in eosinophils of patients with certain malignancies, especially those seen in acute myelomonocytic leukemia with abnormal eosinophils (FAB class M4eo). In order to understand the pathogenesis of these abnormalities, four enzymes, characteristic of the eosinophil, were studied in HL-60 promyelocytic leukemia cells at various stages of eosinophilic differentiation. Using biochemical and ultrahistochemical techniques, the following differences from normal eosinophil development were demonstrated. First, both myeloperoxidase and eosinophil peroxidase coexisted in the population of maturing HL-60 eosinophils. Second, the granules formed from the condensation of material in vacuoles which were derived from dilated segments of the endoplasmic reticulum; the role of the Golgi apparatus in processing of peroxidase appeared minimal. Third, low levels of lysophospholipase and arylsulfatase were present in the cells compared to normal eosinophils. Finally, crystallizations resembling precursor structures of Auer rods appeared in the granules of about 5% of the cells. These findings suggest that several disorders of the control of protein synthesis and processing exist in HL-60 eosinophils which may be responsible for the abnormal granule morphology and histochemistry.

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0160 : Critical role of PTP1B in endoplasmic reticulum stress-induced endothelial dysfunction

Archives of Cardiovascular Diseases Supplements ◽

10.1016/s1878-6480(16)30489-x ◽

2016 ◽

Vol 8 (3) ◽

pp. 250

Author(s):

Pierre-Alain Thiébaut ◽

Eugénie Delile ◽

David Coquerel ◽

Fabienne Tamion ◽

Vincent Richard

Keyword(s):

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Endoplasmic Reticulum Stress ◽

Critical Role

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Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

Antioxidants and Redox Signaling ◽

10.1089/ars.2014.6122 ◽

2015 ◽

Vol 23 (9) ◽

pp. 695-710 ◽

Cited By ~ 38

Author(s):

Lin-Hao Xu ◽

Hui Xie ◽

Zhi-Hui Shi ◽

Li-Da Du ◽

Yun-Kwok Wing ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Synaptic Plasticity ◽

Endoplasmic Reticulum Stress ◽

Intermittent Hypoxia ◽

Critical Role ◽

Chronic Intermittent Hypoxia ◽

Long Term Memory ◽

Term Memory

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ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

Nature Communications ◽

10.1038/s41467-020-19352-1 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Ramesh B. Kasetti ◽

Pinkal D. Patel ◽

Prabhavathi Maddineni ◽

Shruti Patil ◽

Charles Kiehlbauch ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Protein Synthesis ◽

Intraocular Pressure ◽

Mouse Models ◽

Client Protein ◽

Iop Elevation ◽

Human And Mouse ◽

Protein Load

Abstract The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway.

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