The Ca<sup>2+</sup>‐binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6

Parks, Steven Z.; Gao, Tian; Awuapura, Natalia Jimenez; Ayathamattam, Joseph; Chabosseau, Pauline; Kalvakolanu, Dhananjaya V.; Valdivia, Héctor H.; Rutter, Guy A.; Leclerc, Isabelle

doi:10.1002/1873-3468.14101

Cited by 5 publications

(2 citation statements)

References 64 publications

(86 reference statements)

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“…Sorcin null HEK293 cells, generated by CRISPR/Cas9 gene editing, have been described in (Parks et al, 2021). HEK293 cells, seeded in 6-well plates, were transfected with 2 μg LepRb-HA plasmid, encoding full length clone DNA of Human leptin receptor, transcript variant 1 with C terminal HA tag (Sino-Biologicals, # HG10322-CY), using Xfect ™ Transfection Reagent (Takara Bio) according to manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

Parks

Rutter

Leclerc

2022

Preprint

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Background: Soluble Resistance Related Calcium Binding Protein (sorcin) is a calcium (Ca2+) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca2+ stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic β-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic β-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca2+ dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. This could potentially contribute to the diminished satiety typically observed in overweight individuals. Aim: To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity. Methods: Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were used. Body weight, food intake and EchoMRI body composition were measured in vivo whereas qRT-PCR analysis of sorcin and ER stress markers expression were performed on the arcuate nucleus of the hypothalamus. Leptin signalling through STAT3 phosphorylation was measured by Western blots on sorcin-null HEK293 cells, engineered by CRISPR/Cas9, and transfected with leptin receptor (LepRb). Results: Sorcin expression was not influenced in the arcuate nucleus (ARC) of the hypothalamus by diet-induced obesity. Whole-body sorcin ablation did not cause ARC ER stress nor changes in body weight, body composition or food intake in C57BL/6 male mice exposed to a high-fat, high-sugar diet. STAT3 phosphorylation (Y705) in response to leptin was not impaired in sorcin-null HEK293 cells. Conclusion: In our model, whole body sorcin ablation did not increase hypothalamic ER stress nor influenced food intake or body weight.

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Section: Methodsmentioning

confidence: 99%

Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

Parks

Rutter

Leclerc

2022

Preprint

Self Cite

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“…supplemented with penicillin (100 IU/mL), streptomycin (100 µg/mL), L glutamine (4 mM) and FBS (Sigma Aldrich) 10% (vol/vol) in a humidi ed chamber at 37°C with 5% CO 2 .Sorcin null HEK293 cells, generated by CRISPR/Cas9 gene editing, have been described in(Parks et al, 2021). HEK293 cells, seeded in 6-well plates, were transfected with 2 µg LepRb-HA plasmid, encoding full length clone DNA of Human leptin receptor, transcript variant 1 with C terminal HA tag (Sino-Biologicals, # HG10322-CY), using Xfect™ Transfection Reagent (Takara Bio) according to manufacturer's instructions.…”

mentioning

confidence: 99%

Effects of whole-body sorcin knockout on body weight and hypothalamic ER-stress in C57BL/6 male mice fed a westernized diet

Parks

Rutter

Leclerc

2022

Preprint

Self Cite

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Background Soluble Resistance Related Calcium Binding Protein (sorcin) is a calcium (Ca2+) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca2+ stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic β-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic β-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca2+ dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. Aim To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity. Methods Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were used. Body weight, food intake and EchoMRI body composition were measured in vivo whereas qRT-PCR analysis of sorcin and ER stress markers expression were performed on the arcuate nucleus of the hypothalamus. Leptin signalling through STAT3 phosphorylation was measured by Western blots on sorcin-null HEK293 cells, engineered by CRISPR/Cas9, and transfected with leptin receptor (LepRb). Results Sorcin expression was not influenced in the arcuate nucleus (ARC) of the hypothalamus by diet-induced obesity. Whole-body sorcin ablation did not cause ARC ER stress nor changes in body weight, body composition or food intake in C57BL/6 male mice exposed to a high-fat, high-sugar diet. STAT3 phosphorylation (Y705) in response to leptin was not impaired in sorcin-null HEK293 cells. Conclusion In our model, whole body sorcin ablation did not increase hypothalamic ER stress nor influenced food intake or body weight.

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Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins

Gonçalves

Sesterheim

Wartchow

et al. 2022

Front. Cell. Neurosci.

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We are living in a terrifying pandemic caused by Sars-CoV-2, in which patients with diabetes mellitus have, from the beginning, been identified as having a high risk of hospitalization and mortality. This viral disease is not limited to the respiratory system, but also affects, among other organs, the central nervous system. Furthermore, we already know that individuals with diabetes mellitus exhibit signs of astrocyte dysfunction and are more likely to develop cognitive deficits and even dementia. It is now being realized that COVID-19 incurs long-term effects and that those infected can develop several neurological and psychiatric manifestations. As this virus seriously compromises cell metabolism by triggering several mechanisms leading to the unfolded protein response (UPR), which involves endoplasmic reticulum Ca2+ depletion, we review here the basis involved in this response that are intimately associated with the development of neurodegenerative diseases. The discussion aims to highlight two aspects—the role of calcium-binding proteins and the role of astrocytes, glial cells that integrate energy metabolism with neurotransmission and with neuroinflammation. Among the proteins discussed are calpain, calcineurin, and sorcin. These proteins are emphasized as markers of the UPR and are potential therapeutic targets. Finally, we discuss the role of drugs widely prescribed to patients with diabetes mellitus, such as statins, metformin, and calcium channel blockers. The review assesses potential neuroprotection mechanisms, focusing on the UPR and the restoration of reticular Ca2+ homeostasis, based on both clinical and experimental data.

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The Ca²⁺‐binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6

Cited by 5 publications

References 64 publications

Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

Effects of whole-body sorcin knockout on body weight and hypothalamic ER-stress in C57BL/6 male mice fed a westernized diet

Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins

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The Ca2+‐binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6

Cited by 5 publications

References 64 publications

Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

Effects of whole-body sorcin knockout on body weight and hypothalamic ER-stress in C57BL/6 male mice fed a westernized diet

Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins

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The Ca²⁺‐binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6