Endoplasmic Reticulum Stress and Neurodegeneration in Rats Neonatally Infected with Borna Disease Virus

ABSTRACT Borna disease virus infection of neonatal rats results in a characteristic behavioral syndrome and apoptosis of subsets of neurons in the hippocampus and cerebellum (neonatal Borna disease [NBD]). The cellular mechanisms leading to neurodevelopmental damage in NBD have not been fully elucidated. Insights into this model may have general implications for understanding the pathogenesis of virus-associated neurodevelopmental damage. Here we report the presence of endoplasmic reticulum (ER) stress markers and activation of the unfolded protein response in the NBD hippocampus and cerebellum. Specific findings included enhanced PERK-mediated phosphorylation of eif2α and concomitant regulation of ATF4 translation; IRE1-mediated splicing of XBP1 mRNA; and cleavage of the ATF6 protein in NBD rat brains. We found evidence for regional and cell type-specific divergence in the expression of ER stress-induced proapoptotic and quality control signals. Our results demonstrate that ER stress induction in death-susceptible Purkinje neurons in NBD is associated with the expression of the proapoptotic molecule CHOP in the absence of compensatory expression of the ER quality control molecules Bip and protein disulfide isomerase. In contrast, ER stress in death-resistant astrocytes is associated with complementary expression of CHOP and ER quality control signals. These results implicate an imbalance between ER stress-mediated apoptosis and survival signaling as a critical determinant of neural cell fate in NBD.

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A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during stress

eLife ◽

10.7554/elife.58396 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 10

Author(s):

Madlen Stephani ◽

Lorenzo Picchianti ◽

Alexander Gajic ◽

Rebecca Beveridge ◽

Emilio Skarwan ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Mammalian Cells ◽

Control Mechanisms ◽

Receptor Complex ◽

Er Quality Control ◽

Proteotoxic Stress ◽

Quality Control Mechanism ◽

Passenger Proteins

Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the endoplasmic reticulum (ER). Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control in the ER.

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Dilated Cardiomyopathy Caused by Aberrant Endoplasmic Reticulum Quality Control in Mutant KDEL Receptor Transgenic Mice

Molecular and Cellular Biology ◽

10.1128/mcb.24.18.8007-8017.2004 ◽

2004 ◽

Vol 24 (18) ◽

pp. 8007-8017 ◽

Cited By ~ 117

Author(s):

Hiromichi Hamada ◽

Masashi Suzuki ◽

Shigeki Yuasa ◽

Naoya Mimura ◽

Norihiro Shinozuka ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Transgenic Mice ◽

Er Stress ◽

Dilated Cardiomyopathy ◽

Protein Aggregates ◽

Mutant Mice ◽

Er Quality Control ◽

Kdel Receptor

ABSTRACT Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca2+ current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.

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Cell Entry of Borna Disease Virus Follows a Clathrin-Mediated Endocytosis Pathway That Requires Rab5 and Microtubules

Journal of Virology ◽

10.1128/jvi.00990-09 ◽

2009 ◽

Vol 83 (20) ◽

pp. 10406-10416 ◽

Cited By ~ 32

Author(s):

Roberto Clemente ◽

Juan C. de la Torre

Keyword(s):

Disease Virus ◽

Critical Role ◽

Cell Entry ◽

Surface Glycoprotein ◽

Specific Cell ◽

Critical Determinant ◽

Borna Disease Virus ◽

Glycoprotein G ◽

The Central Nervous System ◽

Borna Disease

ABSTRACT Borna disease virus (BDV), the prototypic member of the Bornaviridae family within the order Mononegavirales, exhibits high neurotropism and provides an important and unique experimental model system for studying virus-cell interactions within the central nervous system. BDV surface glycoprotein (G) plays a critical role in virus cell entry via receptor-mediated endocytosis, and therefore, G is a critical determinant of virus tissue and cell tropism. However, the specific cell pathways involved in BDV cell entry have not been determined. Here, we provide evidence that BDV uses a clathrin-mediated, caveola-independent cell entry pathway. We also show that BDV G-mediated fusion takes place at an optimal pH of 6.0 to 6.2, corresponding to an early-endosome compartment. Consistent with this finding, BDV cell entry was Rab5 dependent but Rab7 independent and exhibited rapid fusion kinetics. Our results also uncovered a key role for microtubules in BDV cell entry, whereas the integrity and dynamics of actin cytoskeleton were not required for efficient cell entry of BDV.

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Chaperone-Mediated Reflux of Secretory Proteins to the Cytosol During Endoplasmic Reticulum Stress

10.1101/562306 ◽

2019 ◽

Author(s):

Aeid Igbaria ◽

Philip I. Merksamer ◽

Ala Trusina ◽

Firehiwot Tilahun ◽

Jefferey R. Johnson ◽

...

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Secretory Pathway ◽

Protein Quality ◽

Fluorescent Protein ◽

Control Process ◽

Secretory Proteins ◽

Er Quality Control ◽

Quality Control Process

ABSTRACTDiverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such “ER stress”, we employed an ER-targeted, redox-responsive, green fluorescent protein—eroGFP—that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress agents cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to “reflux” back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in S. cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and co-chaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER-protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.SIGNIFICANCEApproximately one third of eukaryotic proteins are synthesized on ribosomes attached to the endoplasmic reticulum (ER) membrane. Many of these polypeptides co- or post-translationally translocate into the ER, wherein they fold and mature. An ER quality-control system proofreads these proteins by facilitating their folding and modification, while eliminating misfolded proteins through ER-associated degradation (ERAD). Yet, the fate of many secretory proteins during ER stress is not completely understood. Here, we uncovered an ER-stress induced “protein reflux” system that delivers intact, folded ER luminal proteins back to the cytosol without degrading them. We found that ER protein reflux works in parallel to ERAD and requires distinct ER-resident and cytosolic chaperones and co-chaperones.

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