GRASP55 regulates mutant huntingtin unconventional secretion and aggregation

AbstractRecent studies demonstrated that the Golgi stacking proteins, GRASPs, especially GRASP55, regulate Golgi-independent unconventional secretion, but the underlying mechanism remains unknown. Here, we used mutant huntingtin (Htt-Q74) as a model system to address this question. Our results demonstrate that Htt secretion is GRASP55- and autophagy-dependent, and is enhanced under stress conditions such as starvation and ER stress. Mechanistically, GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the ERGIC lumen. Moreover, GRASP55 level is upregulated by various stresses to facilitate unconventional secretion, while inhibition of Htt-Q74 secretion by GRASP55 knockout enhances Htt aggregation and toxicity. Lastly, comprehensive secretomic analysis identified novel cargoes secreted by the same unconventional pathway, such as TAGLN, PAICS and PRDX1. This study provides important information on the role of GRASP55 in unconventional protein secretion and Huntington’s disease progression.

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Pivotal Role Of The Interaction Between Herbal Medicines And Gut Microbiota On Disease Treatment

Current Drug Targets ◽

10.2174/1389450121666200324151530 ◽

2020 ◽

Vol 21 ◽

Cited By ~ 1

Author(s):

Tingting Zhao ◽

Zhe Wang ◽

Zhilong Liu ◽

Youhua Xu

Keyword(s):

Cardiovascular Diseases ◽

Gut Microbiota ◽

Neurodegenerative Diseases ◽

Disease Progression ◽

Herbal Medicines ◽

Underlying Mechanism ◽

Disease Treatment ◽

Endocrine Diseases ◽

Health And Disease

: With the recognition of the important role of gut microbiota in both health and disease progression, attempts to modulate its composition as well as its co-metabolism with the organism have attracted special attention. Abundant studies have demonstrated that dysfunction or imbalance of gut microbiota is closely with disease including endocrine diseases, neurodegenerative diseases, tumors, cardiovascular diseases, et al. Herbal medicines have been applied for preventing and treating disease worldwide for hundreds of years. Although the underlying mechanism seems to be complex, one of the important one is through modulating gut microbiota. In this review, co-metabolism between herbal medicines and microbiota, as well as the potential pathways are summarized from most recent published papers.

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A Concise Review on the Role of Endoplasmic Reticulum Stress in the Development of Autoimmunity in Vitiligo Pathogenesis

Frontiers in Immunology ◽

10.3389/fimmu.2020.624566 ◽

2021 ◽

Vol 11 ◽

Author(s):

Shahnawaz D. Jadeja ◽

Jay M. Mayatra ◽

Jayvadan Vaishnav ◽

Nirali Shukla ◽

Rasheedunnisa Begum

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Underlying Mechanism ◽

Tissue Level ◽

Vital Role ◽

Organ Specific ◽

The Unfolded Protein Response ◽

Destruction Of Melanocytes

Vitiligo is characterized by circumscribed depigmented macules in the skin resulting due to the autoimmune destruction of melanocytes from the epidermis. Both humoral as well as cell-mediated autoimmune responses are involved in melanocyte destruction. Several studies including ours have established that oxidative stress is involved in vitiligo onset, while autoimmunity contributes to the disease progression. However, the underlying mechanism involved in programing the onset and progression of the disease remains a conundrum. Based on several direct and indirect evidences, we suggested that endoplasmic reticulum (ER) stress might act as a connecting link between oxidative stress and autoimmunity in vitiligo pathogenesis. Oxidative stress disrupts cellular redox potential that extends to the ER causing the accumulation of misfolded proteins, which activates the unfolded protein response (UPR). The primary aim of UPR is to resolve the stress and restore cellular homeostasis for cell survival. Growing evidences suggest a vital role of UPR in immune regulation. Moreover, defective UPR has been implicated in the development of autoimmunity in several autoimmune disorders. ER stress-activated UPR plays an essential role in the regulation and maintenance of innate as well as adaptive immunity, and a defective UPR may result in systemic/tissue level/organ-specific autoimmunity. This review emphasizes on understanding the role of ER stress-induced UPR in the development of systemic and tissue level autoimmunity in vitiligo pathogenesis and its therapeutics.

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Role of ER Stress in Inflammasome Activation and Non-Alcoholic Fatty Liver Disease Progression

Single Cell Biology ◽

10.4172/2168-9431.1000140 ◽

2016 ◽

Vol 5 (2) ◽

Cited By ~ 1

Author(s):

Cynthia Lebeaupin ◽

Deborah Vallee

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Er Stress ◽

Disease Progression ◽

Fatty Liver Disease ◽

Inflammasome Activation ◽

Alcoholic Fatty Liver ◽

Liver Disease Progression ◽

Alcoholic Fatty Liver Disease

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ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart

Cells ◽

10.3390/cells9092066 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2066

Author(s):

Bianca A. Meyer ◽

Shirin Doroudgar

Keyword(s):

Er Stress ◽

Protein Secretion ◽

Secretory Pathway ◽

Cell Types ◽

Protein Homeostasis ◽

Cell Type ◽

Select Group ◽

And Function ◽

Review Current

Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled “The Role of Proteostasis Derailment in Cardiac Diseases.”

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ER stress contributes to high-fat diet-induced decrease of thyroglobulin and hypothyroidism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00194.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. E510-E518 ◽

Cited By ~ 1

Author(s):

Xiaohan Zhang ◽

Shanshan Shao ◽

Lifang Zhao ◽

Rui Yang ◽

Meng Zhao ◽

...

Keyword(s):

Er Stress ◽

Thyroid Function ◽

High Fat Diet ◽

Control Diet ◽

Underlying Mechanism ◽

Sprague Dawley ◽

High Fat ◽

Sprague Dawley Rats ◽

Rat Thyroid

Recent studies revealed the emerging role of excess uptake of lipids in the development of hypothyroidism. However, the underlying mechanism is largely unknown. We investigated the effect of high-fat diet (HFD) on thyroid function and the role of endoplasmic reticulum (ER) in HFD-induced hypothyroidism. Male Sprague-Dawley rats were fed with HFD or control diet for 18 wk. HFD rats showed an impaired thyroid function, with decreased thyroglobulin (Tg) level. We found the ER stress was triggered in HFD rat thyroid glands and palmitate-treated thyrocytes. Luminal swelling of ER in thyroid epithelial cells of HFD rats was also observed. The rate of Tg degradation increased in palmitate-treated thyrocytes. In addition, applying 4-phenyl butyric acid to alleviate ER stress in HFD rats improved the decrease of Tg and thyroid function. Withdrawal of the HFD improved thyroid function . In conclusion, we demonstrate that ER stress mediates the HFD-induced hypothyroidism, probably by impairing the production of Tg, and attenuation of ER stress improves thyroid function. Our study provides the understanding of how HFD induces hypothyroidism.

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