bims-ershed 2023-03-12 papers

Commun Biol. 2023 Mar 09. 6(1): 252

Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.

Zhuoran Wang, Qiang Li, Brad J Kolls, Brian Mace, Shu Yu, Xuan Li, Wei Liu, Eduardo Chaparro, Yuntian Shen, Lihong Dang, Ángela Del Águila, Joshua D Bernstock, Kory R Johnson, Junjie Yao, William C Wetsel, Scott D Moore, Dennis A Turner, Wei Yang.

The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box-binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulated) in the brain, including several GABAA receptor genes that are notably downregulated. Finally, whole-cell patch clamp analysis reveals a significant reduction in both spontaneous and tonic GABAergic inhibitory responses in Xbp1s-expressing neurons. Taken together, our findings unravel a link between XBP1s signaling and seizure occurrence.

DOI: https://doi.org/10.1038/s42003-023-04594-8

Front Aging Neurosci. 2023 ;15 1047897

Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.

Yu-Mi Jeon, Younghwi Kwon, Shinrye Lee, Hyung-Jun Kim.

The endoplasmic reticulum (ER) is a major organelle involved in protein quality control and cellular homeostasis. ER stress results from structural and functional dysfunction of the organelle, along with the accumulation of misfolded proteins and changes in calcium homeostasis, it leads to ER stress response pathway such as unfolded protein response (UPR). Neurons are particularly sensitive to the accumulation of misfolded proteins. Thus, the ER stress is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion disease and motor neuron disease (MND). Recently, the complex involvement of ER stress pathways has been demonstrated in experimental models of amyotrophic lateral sclerosis (ALS)/MND using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive response to ER stress. Here, we aim to provide recent evidence demonstrating that the ER stress pathway is an essential pathological mechanism of ALS. In addition, we also provide therapeutic strategies that can help treat diseases by targeting the ER stress pathway.

Keywords: amyotrophic lateral sclerosis; endoplasmic reticulum stress; motor neuron disease; therapeutic target; unfolded protein response

DOI: https://doi.org/10.3389/fnagi.2023.1047897

Front Endocrinol (Lausanne). 2023 ;14 1124405

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome.

Hiroshi Koike, Miyuki Harada, Akari Kusamoto, Zixin Xu, Tsurugi Tanaka, Nanoka Sakaguchi, Chisato Kunitomi, Jerilee M K Azhary, Nozomi Takahashi, Yoko Urata, Yutaka Osuga.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this group, and the most common cause of anovulatory infertility. Although its etiology remains unclear, recent research has revealed the critical role of endoplasmic reticulum (ER) stress in the pathophysiology of PCOS. ER stress is defined as a condition in which unfolded or misfolded proteins accumulate in the ER because of an imbalance in the demand for protein folding and the protein-folding capacity of the ER. ER stress results in the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which regulates various cellular activities. In principle, the UPR restores homeostasis and keeps the cell alive. However, if the ER stress cannot be resolved, it induces programmed cell death. ER stress has recently been recognized to play diverse roles in both physiological and pathological conditions of the ovary. In this review, we summarize current knowledge of the roles of ER stress in the pathogenesis of PCOS. ER stress pathways are activated in the ovaries of both a mouse model of PCOS and in humans, and local hyperandrogenism in the follicular microenvironment associated with PCOS is responsible for activating these. The activation of ER stress contributes to the pathophysiology of PCOS through multiple effects in granulosa cells. Finally, we discuss the potential for ER stress to serve as a novel therapeutic target for PCOS.

Keywords: endoplasmic reticulum stress (ER stress); follicular microenvironment; ovary; pathophysiology; polycystic ovary syndrome (PCOS); unfolded protein response (UPR)

DOI: https://doi.org/10.3389/fendo.2023.1124405

Sci Immunol. 2023 Mar 17. 8(81): eabn7993

An XBP1s-PIM-2 positive feedback loop controls IL-15-mediated survival of natural killer cells.

Shoubao Ma, Jingjing Han, Zhenlong Li, Sai Xiao, Jianying Zhang, Jiazhuo Yan, Tingting Tang, Tasha Barr, Andrew S Kraft, Michael A Caligiuri, Jianhua Yu.

Spliced X-box-binding protein 1 (XBP1s) is an essential transcription factor downstream of interleukin-15 (IL-15) and AKT signaling, which controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms, especially the downstream targets of XBP1s, remain unknown. In this study, by using XBP1 conditional knockout mice, we found that XBP1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanistically, XBP1s regulates homeostatic NK cell survival by targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr58. In addition, XBP1s enhances the effector functions and antitumor immunity of NK cells by recruiting T-bet to the promoter region of Ifng. Collectively, our findings identify a previously unknown mechanism by which IL-15-XBP1s signaling regulates the survival and effector functions of NK cells.

DOI: https://doi.org/10.1126/sciimmunol.abn7993