Cell Death & Differentiation

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ISSN / EISSN : 1350-9047 / 1476-5403
Current Publisher: Springer Science and Business Media LLC (10.1038)
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Peng Tang, Sam Virtue, Jian Yi Gerald Goie, Chin Wen Png, Jing Guo, Ying Li, Huipeng Jiao, Yen Leong Chua, Mark Campbell, José Maria Moreno-Navarrete, et al.
Cell Death & Differentiation pp 1-14; doi:10.1038/s41418-021-00798-9

Abstract:
Dysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity-associated disorders remains unclear. Here, we show that IRF3 expression in human adipose tissues is positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse pre-adipocytes, deficiency of IRF3 results in increased expression of PPARγ and PPARγ-mediated adipogenic genes, leading to increased adipogenesis and altered adipocyte functionality. The IRF3 knockout (KO) mice develop obesity, insulin resistance, glucose intolerance, and eventually type 2 diabetes with aging, which is associated with the development of white adipose tissue (WAT) inflammation. Increased macrophage accumulation with M1 phenotype which is due to the loss of IFNβ-mediated IL-10 expression is observed in WAT of the KO mice compared to that in wild-type mice. Bone-marrow reconstitution experiments demonstrate that the nonhematopoietic cells are the primary contributors to the development of obesity and both hematopoietic and nonhematopoietic cells contribute to the development of obesity-related complications in IRF3 KO mice. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications and hence, could be a potential target for therapeutic interventions for the prevention and treatment of obesity-associated metabolic disorders.
, Maria Zerche, Ana Patricia Kutschat, Asha Nair, Zhenqing Ye, Dominik Saul, Maximilian von Heesen, Jessica J. Friton, Ana Carolina Schwarzer, Nadia Paglilla, et al.
Cell Death & Differentiation pp 1-15; doi:10.1038/s41418-021-00808-w

Abstract:
Despite the identification of several genetic factors linked to increased susceptibility to inflammatory bowel disease (IBD), underlying molecular mechanisms remain to be elucidated in detail. The ubiquitin ligases RNF20 and RNF40 mediate the monoubiquitination of histone H2B at lysine 120 (H2Bub1) and were shown to play context-dependent roles in the development of inflammation. Here, we aimed to examine the function of the RNF20/RNF40/H2Bub1 axis in intestinal inflammation in IBD patients and mouse models. For this purpose, intestinal sections from IBD patients were immunohistochemically stained for H2Bub1. Rnf20 or Rnf40 were conditionally deleted in the mouse intestine and mice were monitored for inflammation-associated symptoms. Using mRNA-seq and chromatin immunoprecipitation (ChIP)-seq, we analyzed underlying molecular pathways in primary intestinal epithelial cells (IECs) isolated from these animals and confirmed these findings in IBD resection specimens using ChIP-seq.The majority (80%) of IBD patients displayed a loss of H2Bub1 levels in inflamed areas and the intestine-specific deletion of Rnf20 or Rnf40 resulted in spontaneous colorectal inflammation in mice. Consistently, deletion of Rnf20 or Rnf40 promoted IBD-associated gene expression programs, including deregulation of various IBD risk genes in these animals. Further analysis of murine IECs revealed that H3K4me3 occupancy and transcription of the Vitamin D Receptor (Vdr) gene and VDR target genes is RNF20/40-dependent. Finally, these effects were confirmed in a subgroup of Crohn’s disease patients which displayed epigenetic and expression changes in RNF20/40-dependent gene signatures. Our findings reveal that loss of H2B monoubiquitination promotes intestinal inflammation via decreased VDR activity thereby identifying RNF20 and RNF40 as critical regulators of IBD.
Xin Wang, Uris Ros, Deepti Agrawal, Eva C. Keller, Julia Slotta-Huspenina, Veronika Dill, Bo Shen, , Tobias Herold, , et al.
Cell Death & Differentiation pp 1-16; doi:10.1038/s41418-021-00811-1

Abstract:
The blockade of cellular differentiation represents a hallmark of acute myeloid leukemia (AML), which is largely attributed to the dysfunction of lineage-specific transcription factors controlling cellular differentiation. However, alternative mechanisms of cellular differentiation programs in AML remain largely unexplored. Here we report that mixed lineage kinase domain-like protein (MLKL) contributes to the cellular differentiation of transformed hematopoietic progenitor cells in AML. Using gene-targeted mice, we show that MLKL facilitates the release of granulocyte colony-stimulating factor (G-CSF) by controlling membrane permeabilization in leukemic cells. Mlkl −/− hematopoietic stem and progenitor cells released reduced amounts of G-CSF while retaining their capacity for CSF3 (G-CSF) mRNA expression, G-CSF protein translation, and G-CSF receptor signaling. MLKL associates with early endosomes and controls G-CSF release from intracellular storage by plasma membrane pore formation, whereas cell death remained unaffected by loss of MLKL. Of note, MLKL expression was significantly reduced in AML patients, specifically in those with a poor-risk AML subtype. Our data provide evidence that MLKL controls myeloid differentiation in AML by controlling the release of G-CSF from leukemic progenitor cells.
Christian Bassi, Jerome Fortin, Bryan E. Snow, Andrew Wakeham, Jason Ho, Jillian Haight, Annick You-Ten, Emily Cianci, Luke Buckler, Chiara Gorrini, et al.
Cell Death & Differentiation pp 1-16; doi:10.1038/s41418-021-00799-8

Abstract:
The tumor suppressor PTEN is disrupted in a large proportion of cancers, including in HER2-positive breast cancer, where its loss is associated with resistance to therapy. Upon genotoxic stress, ataxia telangiectasia mutated (ATM) is activated and phosphorylates PTEN on residue 398. To elucidate the physiological role of this molecular event, we generated and analyzed knock-in mice expressing a mutant form of PTEN that cannot be phosphorylated by ATM (PTEN-398A). This mutation accelerated tumorigenesis in a model of HER2-positive breast cancer. Mammary tumors in bi-transgenic mice carrying MMTV-neu and Pten 398A were characterized by DNA damage accumulation but reduced apoptosis. Mechanistically, phosphorylation of PTEN at position 398 is essential for the proper activation of the S phase checkpoint controlled by the PI3K–p27Kip1–CDK2 axis. Moreover, we linked these defects to the impaired ability of the PTEN-398A protein to relocalize to the plasma membrane in response to genotoxic stress. Altogether, our results uncover a novel role for ATM-dependent PTEN phosphorylation in the control of genomic stability, cell cycle progression, and tumorigenesis.
Chen Wang, Ziyu Shi, Yuqian Zhang, Mingyue Li, Jie Zhu, , , Jiangning Chen
Cell Death & Differentiation pp 1-17; doi:10.1038/s41418-021-00810-2

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Correction
Chenzhong Xu, Nan Xie, Yuanyuan Su, Zhaomeng Sun, Yao Liang, Na Zhang, Doudou Liu, Shuqin Jia, Xiaofang Xing, Limin Han, et al.
Cell Death & Differentiation pp 1-1; doi:10.1038/s41418-021-00806-y

Raquel M. Marques, Maria Gonzalez-Nunez, Mary E. Walker, Esteban A. Gomez, Romain A. Colas, , ,
Cell Death & Differentiation pp 1-21; doi:10.1038/s41418-021-00807-x

Abstract:
Regulatory T-cells (Tregs) are central in the maintenance of homeostasis and resolution of inflammation. However, the mechanisms that govern their differentiation and function are not completely understood. Herein, we demonstrate a central role for the lipid mediator biosynthetic enzyme 15-lipoxygenase (ALOX15) in regulating key aspects of Treg biology. Pharmacological inhibition or genetic deletion of ALOX15 in Tregs decreased FOXP3 expression, altered Treg transcriptional profile and shifted their metabolism. This was linked with an impaired ability of Alox15-deficient cells to exert their pro-resolving actions, including a decrease in their ability to upregulate macrophage efferocytosis and a downregulation of interferon gamma expression in Th1 cells. Incubation of Tregs with the ALOX15-derived specilized pro-resolving mediators (SPM)s Resolvin (Rv)D3 and RvD5n-3 DPA rescued FOXP3 expression in cells where ALOX15 activity was inhibited. In vivo, deletion of Alox15 led to increased vascular lipid load and expansion of Th1 cells in mice fed western diet, a phenomenon that was reversed when Alox15-deficient mice were reconstituted with wild type Tregs. Taken together these findings demonstrate a central role of pro-resolving lipid mediators in governing the differentiation of naive T-cells to Tregs.
Xi Sheng Rao, Xiao Xia Cong, Xiu Kui Gao, Yin Pu Shi, Lin Jing Shi, Jian Feng Wang, Chen-Yao Ni, Ming Jie He, , Cong Yi, et al.
Cell Death & Differentiation pp 1-21; doi:10.1038/s41418-021-00809-9

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, Lei Shi, Peter Magee, Sudhakar Sahoo, ,
Cell Death & Differentiation pp 1-17; doi:10.1038/s41418-021-00777-0

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