bims-nimamd 2023-01-29 papers

bims-nimamd

Biomed News

on Neuroimmunity and neuroinflammation in ageing and metabolic disease

Issue of 2023–01–29
forty papers selected by
Fawaz Alzaïd, Sorbonne Université

Aging in the CSF.
Changing the baseline.
Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B.
RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8.
Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity.
Remembrance of things past.
Chromatin complex dependencies reveal targeting opportunities in leukemia.
STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection.
Deciphering the multi-scale, quantitative cis-regulatory code.
The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice.
Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores Caenorhabditis elegans development in the absence of SWI/SNF function.
In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice.
Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis.
Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS.
Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose.
Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice.
Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development.
MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.
SUMOylation of HNRNPA2B1 modulates RPA dynamics during unperturbed replication and genotoxic stress responses.
Intrathymic dendritic cell-biased precursors promote human T cell lineage specification through IRF8-driven transmembrane TNF.
How sexual touch triggers pleasant sensations in mice.
Immuno-metabolic control of the balance between Th17-polarized and regulatory T-cells during HIV infection.
A census of complexes formed by mitochondrial proteins.
Neutrophil-activating therapy for the treatment of cancer.
Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.
Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.
Multi-omics profiling of cholangiocytes reveals sex-specific chromatin state dynamics during hepatic cystogenesis in polycystic liver disease.
A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene.
MME+ fibro-adipogenic progenitors are the dominant adipogenic population during fatty infiltration in human skeletal muscle.
The antidiabetic drug metformin aids bacteria in hijacking vitamin B12 from the environment through RcdA.
How your brain stays on task when sizing someone up.
Tex2 is required for lysosomal functions at TMEM55-dependent ER membrane contact sites.
Flu, MERS and Ebola - the disease outbreaks most frequently reported.
IFN-Induced Protein with Tetratricopeptide Repeats 2 Limits Autoimmune Inflammation by Regulating Myeloid Cell Activation and Metabolic Activity.
Human NK cells control HIV infection in a mouse model.
Murine breast cancers disorganize the liver transcriptome in a zonated manner.
Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain.
Metabolism, homeostasis, and aging.
A FRET-based respirasome assembly screen identifies spleen tyrosine kinase as a target to improve muscle mitochondrial respiration and exercise performance in mice.
A cellular hierarchy of Notch and Kras signaling controls cell fate specification in the developing mouse salivary gland.

Nat Immunol. 2023 Jan 27.

Aging in the CSF.

Stephanie Houston.

DOI: https://doi.org/10.1038/s41590-023-01431-2
Nat Immunol. 2023 Jan 27.

Changing the baseline.

Ioana Visan.

DOI: https://doi.org/10.1038/s41590-023-01435-y
Nat Commun. 2023 Jan 23. 14(1): 371

Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B.

Simon Andrews, Christel Krueger, Maravillas Mellado-Lopez, Myriam Hemberger, Wendy Dean, Vicente Perez-Garcia, Courtney W Hanna.

DNA methylation is a repressive epigenetic modification that is essential for development, exemplified by the embryonic and perinatal lethality observed in mice lacking de novo DNA methyltransferases (DNMTs). Here we characterise the role for DNMT3A, 3B and 3L in gene regulation and development of the mouse placenta. We find that each DNMT establishes unique aspects of the placental methylome through targeting to distinct chromatin features. Loss of Dnmt3b results in de-repression of germline genes in trophoblast lineages and impaired formation of the maternal-foetal interface in the placental labyrinth. Using Sox2-Cre to delete Dnmt3b in the embryo, leaving expression intact in placental cells, the placental phenotype was rescued and, consequently, the embryonic lethality, as Dnmt3b null embryos could now survive to birth. We conclude that de novo DNA methylation by DNMT3B during embryogenesis is principally required to regulate placental development and function, which in turn is critical for embryo survival.

DOI: https://doi.org/10.1038/s41467-023-36019-9
Sci Adv. 2023 Jan 25. 9(4): eadd6097

RIPK1 blocks T cell senescence mediated by RIPK3 and caspase-8.

Takayuki Imanishi, Midori Unno, Natsumi Yoneda, Yasutaka Motomura, Miho Mochizuki, Takaharu Sasaki, Manolis Pasparakis, Takashi Saito.

Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation. Here, we show that T cell-specific RIPK1 deficiency in mice leads to the premature senescence of T cells and induces various age-related diseases, resulting in premature death. RIPK1 deficiency causes higher basal activation of mTORC1 (mechanistic target of rapamycin complex 1) that drives enhanced cytokine production, induction of senescence-related genes, and increased activation of caspase-3/7, which are restored by inhibition of mTORC1. Critically, normal aged T cells exhibit similar phenotypes and responses. Mechanistically, a combined deficiency of RIPK3 and caspase-8 inhibition restores the impaired proliferative responses; the elevated activation of Akt, mTORC1, extracellular signal-regulated kinase, and caspase-3/7; and the increased expression of senescence-related genes in RIPK1-deficient CD4 T cells. Last, we revealed that the senescent phenotype of RIPK1-deficient and aged CD4 T cells is restored in the normal tissue environment. Thus, we have clarified the function of RIPK3 and caspase-8 in inducing CD4 T cell senescence, which is modulated by environmental signals.

DOI: https://doi.org/10.1126/sciadv.add6097
Nat Commun. 2023 Jan 21. 14(1): 351

Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity.

Yue Liu, Yue Yang, Chenying Xu, Jianxing Liu, Jiale Chen, Guoqing Li, Bin Huang, Yi Pan, Yanfeng Zhang, Qiong Wei, Stephen J Pandol, Fangfang Zhang, Ling Li, Liang Jin.

Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.

DOI: https://doi.org/10.1038/s41467-023-35998-z
Nat Immunol. 2023 Jan 27.

Remembrance of things past.

Laurie A Dempsey.

DOI: https://doi.org/10.1038/s41590-023-01434-z
Nat Commun. 2023 Jan 27. 14(1): 448

Chromatin complex dependencies reveal targeting opportunities in leukemia.

Fadi J Najm, Peter DeWeirdt, Molly M Moore, Samantha M Bevill, Chadi A El Farran, Kevin A Macias, Mudra Hegde, Amanda L Waterbury, Brian B Liau, Peter van Galen, John G Doench, Bradley E Bernstein.

Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.

DOI: https://doi.org/10.1038/s41467-023-36150-7
J Exp Med. 2023 Apr 03. pii: e20220686. [Epub ahead of print]220(4):

STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection.

Qinli Sun, Xiaohong Zhao, Ruifeng Li, Dingfeng Liu, Birui Pan, Bowen Xie, Xinxin Chi, Dongli Cai, Peng Wei, Wei Xu, Kun Wei, Zixuan Zhao, Yujie Fu, Ling Ni, Chen Dong.

In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remains not well understood. Here, we found that STAT3 signaling plays essential roles in promoting intratumor Texterm cell development by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while it suppresses those expressed by the progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at the effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits the development of more effective immunotherapies against tumors.

DOI: https://doi.org/10.1084/jem.20220686
Mol Cell. 2023 Jan 13. pii: S1097-2765(22)01215-1. [Epub ahead of print]

Deciphering the multi-scale, quantitative cis-regulatory code.

Seungsoo Kim, Joanna Wysocka.

  Uncovering the cis-regulatory code that governs when and how much each gene is transcribed in a given genome and cellular state remains a central goal of biology. Here, we discuss major layers of regulation that influence how transcriptional outputs are encoded by DNA sequence and cellular context. We first discuss how transcription factors bind specific DNA sequences in a dosage-dependent and cooperative manner and then proceed to the cofactors that facilitate transcription factor function and mediate the activity of modular cis-regulatory elements such as enhancers, silencers, and promoters. We then consider the complex and poorly understood interplay of these diverse elements within regulatory landscapes and its relationships with chromatin states and nuclear organization. We propose that a mechanistically informed, quantitative model of transcriptional regulation that integrates these multiple regulatory layers will be the key to ultimately cracking the cis-regulatory code.

Keywords:  RNA polymerase II; activation domain; chromatin; cis-regulatory code; cis-regulatory element; coactivator; cofactor; corepressor; enhancer; gene regulation; insulator; nucleosome; pioneer factor; promoter; regulatory domain; repression domain; silencer; topologically associating domain; transcription; transcription factor

DOI:  https://doi.org/10.1016/j.molcel.2022.12.032
Nat Commun. 2023 Jan 23. 14(1): 167

The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice.

Yuka Inaba, Emi Hashiuchi, Hitoshi Watanabe, Kumi Kimura, Yu Oshima, Kohsuke Tsuchiya, Shin Murai, Chiaki Takahashi, Michihiro Matsumoto, Shigetaka Kitajima, Yasuhiko Yamamoto, Masao Honda, Shun-Ichiro Asahara, Kim Ravnskjaer, Shin-Ichi Horike, Shuichi Kaneko, Masato Kasuga, Hiroyasu Nakano, Kenichi Harada, Hiroshi Inoue.

Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis. In severe hepatic steatosis, after partial hepatectomy, hepatic ATF3-deficient or -overexpressing mice display decreased or increased RIPK3 expression and necroptosis, respectively. In cultured hepatocytes, ATF3 changes TNFα-dependent cell death mode from apoptosis to necroptosis, as revealed by live-cell imaging. In non-alcoholic steatohepatitis (NASH) mice, hepatic ATF3 deficiency suppresses RIPK3 expression and hepatocellular death. In human NASH, hepatocellular damage is correlated with the frequency of hepatocytes expressing ATF3 or RIPK3, which overlap frequently. ATF3-dependent RIPK3 induction, causing a modal shift of hepatocellular death, can be a therapeutic target for steatosis-induced liver damage, including NASH.

DOI: https://doi.org/10.1038/s41467-023-35804-w
Proc Natl Acad Sci U S A. 2023 Jan 31. 120(5): e2217992120

Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores Caenorhabditis elegans development in the absence of SWI/SNF function.

Lisa Lampersberger, Francesca Conte, Subhanita Ghosh, Yutong Xiao, Jonathan Price, David Jordan, David Q Matus, Peter Sarkies, Petra Beli, Eric A Miska, Nicholas O Burton.

  SWItch/sucrose non-fermenting (SWI/SNF) complexes are a family of chromatin remodelers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here, we identify an alanine-to-valine-causing mutation in the SWI/SNF subunit snfc-5 (SMARCB1 in humans) that prevents embryonic lethality in Caenorhabditis elegans nematodes harboring a loss-of-function mutation in the SWI/SNF subunit swsn-1 (SMARCC1/2 in humans). Furthermore, we found that the combination of this specific mutation in snfc-5 and a loss-of-function mutation in either of the E3 ubiquitin ligases ubr-5 (UBR5 in humans) or hecd-1 (HECTD1 in humans) can restore development to adulthood in swsn-1 loss-of-function mutants that otherwise die as embryos. Using these mutant models, we established a set of 335 genes that are dysregulated in SWI/SNF mutants that arrest their development embryonically but exhibit near wild-type levels of expression in the presence of suppressor mutations that prevent embryonic lethality, suggesting that SWI/SNF promotes development by regulating some subset of these 335 genes. In addition, we show that SWI/SNF protein levels are reduced in swsn-1; snfc-5 double mutants and partly restored to wild-type levels in swsn-1; snfc-5; ubr-5 triple mutants, consistent with a model in which UBR-5 regulates SWI/SNF levels by tagging the complex for proteasomal degradation. Our findings establish a link between two E3 ubiquitin ligases and SWI/SNF function and suggest that UBR5 and HECTD1 could be potential therapeutic targets for the many developmental disorders caused by missense mutations in SWI/SNF subunits.

Keywords:  C. elegans; HECD-1; SWI/SNF; UBR-5; development

DOI:  https://doi.org/10.1073/pnas.2217992120
Nat Biotechnol. 2023 Jan 26.

In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice.

Carine Bouffi, Kathryn A Wikenheiser-Brokamp, Praneet Chaturvedi, Nambirajan Sundaram, Gillian R Goddard, Mark Wunderlich, Nicole E Brown, Janet F Staab, Rachel Latanich, Nicholas C Zachos, Emily M Holloway, Maxime M Mahe, Holly M Poling, Simon Vales, Garrett W Fisher, Jason R Spence, James C Mulloy, Aaron M Zorn, James M Wells, Michael A Helmrath.

Human intestinal organoids (HIOs) derived from pluripotent stem cells provide a valuable model for investigating human intestinal organogenesis and physiology, but they lack the immune components required to fully recapitulate the complexity of human intestinal biology and diseases. To address this issue and to begin to decipher human intestinal-immune crosstalk during development, we generated HIOs containing immune cells by transplanting HIOs under the kidney capsule of mice with a humanized immune system. We found that human immune cells temporally migrate to the mucosa and form cellular aggregates that resemble human intestinal lymphoid follicles. Moreover, after microbial exposure, epithelial microfold cells are increased in number, leading to immune cell activation determined by the secretion of IgA antibodies in the HIO lumen. This in vivo HIO system with human immune cells provides a framework for future studies on infection- or allergen-driven intestinal diseases.

DOI: https://doi.org/10.1038/s41587-022-01558-x
Aging Cell. 2023 Jan 23. e13783

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis.

Jianrui Song, Diana Farris, Paola Ariza, Smriti Moorjani, Mita Varghese, Muriel Blin, Judy Chen, Daniel Tyrrell, Min Zhang, Kanakadurga Singer, Morgan Salmon, Daniel R Goldstein.

  Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr-/- recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors. By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.

Keywords:  atherosclerosis; inflammation; macrophage; monocyte; visceral adipose tissue

DOI:  https://doi.org/10.1111/acel.13783
Nature. 2023 Jan 25.

Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS.

Laura J Pallett, Leo Swadling, Mariana Diniz, Alexander A Maini, Marius Schwabenland, Adrià Dalmau Gasull, Jessica Davies, Stephanie Kucykowicz, Jessica K Skelton, Niclas Thomas, Nathalie M Schmidt, Oliver E Amin, Upkar S Gill, Kerstin A Stegmann, Alice R Burton, Emily Stephenson, Gary Reynolds, Matt Whelan, Jenifer Sanchez, Roel de Maeyer, Clare Thakker, Kornelija Suveizdyte, Imran Uddin, Ana M Ortega-Prieto, Charlotte Grant, Farid Froghi, Giuseppe Fusai, Sabela Lens, Sofia Pérez-Del-Pulgar, Walid Al-Akkad, Giuseppe Mazza, Mahdad Noursadeghi, Arne Akbar, Patrick T F Kennedy, Brian R Davidson, Marco Prinz, Benjamin M Chain, Muzlifah Haniffa, Derek W Gilroy, Marcus Dorner, Bertram Bengsch, Anna Schurich, Mala K Maini.

The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1-4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins-including the lipopolysaccharide receptor complex-from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut-liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.

DOI: https://doi.org/10.1038/s41586-022-05645-6
Nat Commun. 2023 Jan 27. 14(1): 451

Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose.

Lifelines Cohort Study

The genetic regulation of post-prandial glucose levels is poorly understood. Here, we characterise the genetic architecture of blood glucose variably measured within 0 and 24 h of fasting in 368,000 European ancestry participants of the UK Biobank. We found a near-linear increase in the heritability of non-fasting glucose levels over time, which plateaus to its fasting state value after 5 h post meal (h2 = 11%; standard error: 1%). The genetic correlation between different fasting times is > 0.77, suggesting that the genetic control of glucose is largely constant across fasting durations. Accounting for heritability differences between fasting times leads to a ~16% improvement in the discovery of genetic variants associated with glucose. Newly detected variants improve the prediction of fasting glucose and type 2 diabetes in independent samples. Finally, we meta-analysed summary statistics from genome-wide association studies of random and fasting glucose (N = 518,615) and identified 156 independent SNPs explaining 3% of fasting glucose variance. Altogether, our study demonstrates the utility of random glucose measures to improve the discovery of genetic variants associated with glucose homeostasis, even in fasting conditions.

DOI: https://doi.org/10.1038/s41467-023-36013-1
Nat Commun. 2023 Jan 24. 14(1): 390

Long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice.

Tong-Sheng Huang, Teng Wu, Yan-di Wu, Xing-Hui Li, Jing Tan, Cong-Hui Shen, Shi-Jie Xiong, Zi-Qi Feng, Sai-Fei Gao, Hui Li, Wei-Bin Cai.

Statins play an important role in the treatment of diabetic nephropathy. Increasing attention has been given to the relationship between statins and insulin resistance, but many randomized controlled trials confirm that the therapeutic effects of statins on diabetic nephropathy are more beneficial than harmful. However, further confirmation of whether the beneficial effects of chronic statin administration on diabetic nephropathy outweigh the detrimental effects is urgently needed. Here, we find that long-term statin administration may increase insulin resistance, interfere with lipid metabolism, leads to inflammation and fibrosis, and ultimately fuel diabetic nephropathy progression in diabetic mice. Mechanistically, activation of insulin-regulated phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway leads to increased fatty acid synthesis. Furthermore, statins administration increases lipid uptake and inhibits fatty acid oxidation, leading to lipid deposition. Here we show that long-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice.

DOI: https://doi.org/10.1038/s41467-023-35944-z
Nat Commun. 2023 Jan 21. 14(1): 348

Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development.

Xiaochan Xu, Philip Allan Seymour, Kim Sneppen, Ala Trusina, Anuska la Rosa Egeskov-Madsen, Mette Christine Jørgensen, Mogens Høgh Jensen, Palle Serup.

The Notch ligands Jag1 and Dll1 guide differentiation of multipotent pancreatic progenitor cells (MPCs) into unipotent pro-acinar cells (PACs) and bipotent duct/endocrine progenitors (BPs). Ligand-mediated trans-activation of Notch receptors induces oscillating expression of the transcription factor Hes1, while ligand-receptor cis-interaction indirectly represses Hes1 activation. Despite Dll1 and Jag1 both displaying cis- and trans-interactions, the two mutants have different phenotypes for reasons not fully understood. Here, we present a mathematical model that recapitulates the spatiotemporal differentiation of MPCs into PACs and BPs. The model correctly captures cell fate changes in Notch pathway knockout mice and small molecule inhibitor studies, and a requirement for oscillatory Hes1 expression to maintain the multipotent state. Crucially, the model entails cell-autonomous attenuation of Notch signaling by Jag1-mediated cis-inhibition in MPC differentiation. The model sheds light on the underlying mechanisms, suggesting that cis-interaction is crucial for exiting the multipotent state, while trans-interaction is required for adopting the bipotent fate.

DOI: https://doi.org/10.1038/s41467-023-35963-w
EMBO J. 2023 Jan 27. e112309

MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.

Lena Krämer, Niko Dalheimer, Markus Räschle, Zuzana Storchová, Jan Pielage, Felix Boos, Johannes M Herrmann.

  Hundreds of nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. However, the early processes associated with mitochondrial protein targeting remain poorly understood. Here, we show that in Saccharomyces cerevisiae, the cytosol has the capacity to transiently store mitochondrial matrix-destined precursors in dedicated deposits that we termed MitoStores. Competitive inhibition of mitochondrial protein import via clogging of import sites greatly enhances the formation of MitoStores, but they also form during physiological cell growth on nonfermentable carbon sources. MitoStores are enriched for a specific subset of nucleus-encoded mitochondrial proteins, in particular those containing N-terminal mitochondrial targeting sequences. Our results suggest that MitoStore formation suppresses the toxic potential of aberrantly accumulating mitochondrial precursor proteins and is controlled by the heat shock proteins Hsp42 and Hsp104. Thus, the cytosolic protein quality control system plays an active role during the early stages of mitochondrial protein targeting through the coordinated and localized sequestration of mitochondrial precursor proteins.

Keywords:  chaperones; mitochondria; proteasome; protein aggregates; protein translocation

DOI:  https://doi.org/10.15252/embj.2022112309
Mol Cell. 2023 Jan 14. pii: S1097-2765(23)00003-5. [Epub ahead of print]

SUMOylation of HNRNPA2B1 modulates RPA dynamics during unperturbed replication and genotoxic stress responses.

Shouhai Zhu, Jing Hou, Huanyao Gao, Qi Hu, Jake A Kloeber, Jinzhou Huang, Fei Zhao, Qin Zhou, Kuntian Luo, Zheming Wu, Xinyi Tu, Ping Yin, Zhenkun Lou.

  Replication protein A (RPA) is a major regulator of eukaryotic DNA metabolism involved in multiple essential cellular processes. Maintaining appropriate RPA dynamics is crucial for cells to prevent RPA exhaustion, which can lead to replication fork breakage and replication catastrophe. However, how cells regulate RPA availability during unperturbed replication and in response to stress has not been well elucidated. Here, we show that HNRNPA2B1SUMO functions as an endogenous inhibitor of RPA during normal replication. HNRNPA2B1SUMO associates with RPA through recognizing the SUMO-interacting motif (SIM) of RPA to inhibit RPA accumulation at replication forks and impede local ATR activation. Declining HNRNPA2SUMO induced by DNA damage will release nuclear soluble RPA to localize to chromatin and enable ATR activation. Furthermore, we characterize that HNRNPA2B1 hinders homologous recombination (HR) repair via limiting RPA availability, thus conferring sensitivity to PARP inhibitors. These findings establish HNRNPA2B1 as a critical player in RPA-dependent surveillance networks.

Keywords:  ATR; ATRIP; DNA damage; HNRNPA2B1; RPA; SUMOylation; breast cancer; homologous recombination; replication stress

DOI:  https://doi.org/10.1016/j.molcel.2023.01.003
Nat Immunol. 2023 Jan 26.

Intrathymic dendritic cell-biased precursors promote human T cell lineage specification through IRF8-driven transmembrane TNF.

Kai Ling Liang, Juliette Roels, Marieke Lavaert, Tom Putteman, Lena Boehme, Laurentijn Tilleman, Imke Velghe, Valentina Pegoretti, Inge Van de Walle, Stephanie Sontag, Jolien Vandewalle, Bart Vandekerckhove, Georges Leclercq, Pieter Van Vlierberghe, Claude Libert, Filip Van Nieuwerburgh, Roman Fischer, Roland E Kontermann, Klaus Pfizenmaier, Gina Doody, Martin Zenke, Tom Taghon.

The cross-talk between thymocytes and thymic stromal cells is fundamental for T cell development. In humans, intrathymic development of dendritic cells (DCs) is evident but its physiological significance is unknown. Here we showed that DC-biased precursors depended on the expression of the transcription factor IRF8 to express the membrane-bound precursor form of the cytokine TNF (tmTNF) to promote differentiation of thymus seeding hematopoietic progenitors into T-lineage specified precursors through activation of the TNF receptor (TNFR)-2 instead of TNFR1. In vitro recapitulation of TNFR2 signaling by providing low-density tmTNF or a selective TNFR2 agonist enhanced the generation of human T cell precursors. Our study shows that, in addition to mediating thymocyte selection and maturation, DCs function as hematopoietic stromal support for the early stages of human T cell development and provide proof of concept that selective targeting of TNFR2 can enhance the in vitro generation of T cell precursors for clinical application.

DOI: https://doi.org/10.1038/s41590-022-01417-6
Nature. 2023 Jan 24.

How sexual touch triggers pleasant sensations in mice.



Keywords:  Neuroscience

DOI:  https://doi.org/10.1038/d41586-023-00134-w
Cytokine Growth Factor Rev. 2023 Jan 18. pii: S1359-6101(23)00001-1. [Epub ahead of print]

Immuno-metabolic control of the balance between Th17-polarized and regulatory T-cells during HIV infection.

Alexis Yero, Ralph-Sydney Mboumba Bouassa, Petronela Ancuta, Jerome Estaquier, Mohammad-Ali Jenabian.

  Th17-polarized CD4+ effector T-cells together with their immunosuppressive regulatory T-cell (Treg) counterparts, with transcriptional profiles governed by the lineage transcription factors RORγt/RORC2 and FOXP3, respectively, are important gatekeepers at mucosal interfaces. Alterations in the Th17/Treg ratios, due to the rapid depletion of Th17 cells and increased Treg frequencies, are a hallmark of both HIV and SIV infections and a marker of disease progression. The shift in Th17/Treg balance, in favor of increased Treg frequencies, contributes to gut mucosal permeability, immune dysfunction, and microbial translocation, subsequently leading to chronic immune activation/inflammation and disease progression. Of particular interest, Th17 cells and Tregs share developmental routes, with changes in the Th17 versus Treg fate decision influencing the pro-inflammatory versus anti-inflammatory responses. The differentiation and function of Th17 cells and Tregs rely on independent yet complementary metabolic pathways. Several pathways have been described in the literature to be involved in Th17 versus Treg polarization, including 1) the activity of ectonucleotidases CD39/CD73; 2) the increase in TGF-β1 production; 3) a hypoxic environment, and subsequent upregulation in hypoxia-inducible factor-1α (HIF-1α); 4) the increased mTOR activity and glycolysis induction; 5) the lipid metabolism, including fatty acid synthesis, fatty acids oxidation, cholesterol synthesis, and lipid storage, which are regulated by the AMPK, mevalonate and PPARγ pathways; and 6) the tryptophan catabolism. These metabolic pathways are understudied in the context of HIV-1 infection. The purpose of this review is to summarize the current knowledge on metabolic pathways that are dysregulated during HIV-1 infection and their impact on Th17/Treg balance.

Keywords:  AMPK; CD39; CD73; Ectonucleotidases; Glycolysis; HIF-1α; HIV; Hypoxia; IDO-1; Immunometabolism; MTOR; PPAR-γ; Regulatory T-cells (Tregs); TGF-β1; Th17 cells; Tryptophan

DOI:  https://doi.org/10.1016/j.cytogfr.2023.01.001
Nature. 2023 Jan 25.

A census of complexes formed by mitochondrial proteins.



Keywords:  Biochemistry; Cell biology; Metabolism; Proteomics

DOI:  https://doi.org/10.1038/d41586-023-00095-0
Cancer Cell. 2023 Jan 19. pii: S1535-6108(23)00002-8. [Epub ahead of print]

Neutrophil-activating therapy for the treatment of cancer.

Ian L Linde, Tyler R Prestwood, Jingtao Qiu, Genay Pilarowski, Miles H Linde, Xiangyue Zhang, Lei Shen, Nathan E Reticker-Flynn, David Kung-Chun Chiu, Lauren Y Sheu, Simon Van Deursen, Lorna L Tolentino, Wen-Chao Song, Edgar G Engleman.

  Despite their cytotoxic capacity, neutrophils are often co-opted by cancers to promote immunosuppression, tumor growth, and metastasis. Consequently, these cells have received little attention as potential cancer immunotherapeutic agents. Here, we demonstrate in mouse models that neutrophils can be harnessed to induce eradication of tumors and reduce metastatic seeding through the combined actions of tumor necrosis factor, CD40 agonist, and tumor-binding antibody. The same combination activates human neutrophils in vitro, enabling their lysis of human tumor cells. Mechanistically, this therapy induces rapid mobilization and tumor infiltration of neutrophils along with complement activation in tumors. Complement component C5a activates neutrophils to produce leukotriene B4, which stimulates reactive oxygen species production via xanthine oxidase, resulting in oxidative damage and T cell-independent clearance of multiple tumor types. These data establish neutrophils as potent anti-tumor immune mediators and define an inflammatory pathway that can be harnessed to drive neutrophil-mediated eradication of cancer.

Keywords:  C5a; CD40; cancer immunotherapy; complement; leukotriene B4; neutrophil; reactive oxygen species; tumor immunology; tumor necrosis factor; xanthine oxidase

DOI:  https://doi.org/10.1016/j.ccell.2023.01.002
Nat Cell Biol. 2023 Jan 23.

Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.

Elias Adriaenssens, Bob Asselbergh, Pablo Rivera-Mejías, Sven Bervoets, Leen Vendredy, Vicky De Winter, Katrien Spaas, Riet de Rycke, Gert van Isterdael, Francis Impens, Thomas Langer, Vincent Timmerman.

Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.

DOI: https://doi.org/10.1038/s41556-022-01074-9
Nat Commun. 2023 Jan 25. 14(1): 399

Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.

S S Mahalingam, S Jayaraman, N Bhaskaran, E Schneider, F Faddoul, A Paes da Silva, M M Lederman, R Asaad, K Adkins-Travis, L P Shriver, P Pandiyan.

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.

DOI: https://doi.org/10.1038/s41467-023-36163-2
J Hepatol. 2023 Jan 18. pii: S0168-8278(23)00015-6. [Epub ahead of print]

Multi-omics profiling of cholangiocytes reveals sex-specific chromatin state dynamics during hepatic cystogenesis in polycystic liver disease.

Rongjie Ji, Jiayuan Chen, Yuyang Xie, Xudan Dou, Bo Qing, Zhiheng Liu, Yumei Lu, Lin Dang, Xu Zhu, Ying Sun, Xiangjian Zheng, Lirong Zhang, Dong Guo, Yupeng Chen.

   BACKGROUND & AIMS: Cholangiocytes transit from quiescence to hyperproliferation during cystogenesis in polycystic liver disease (PLD), the severity of which displays prominent sex differences. Epigenetic regulation plays important roles in cell state transition. We aimed to investigate the sex-specific epigenetic basis of hepatic cystogenesis and to develop therapeutic strategies targeting epigenetic modifications for PLD treatment.
METHODS: Normal and cystic primary cholangiocytes were isolated from wild type and PLD mice of both genders. Chromatin states were characterized by analyzing chromatin accessibility (ATAC-seq) and multiple histone modifications (ChIP-seq). Differential gene expression was determined by transcriptomic analysis (RNA-seq). Pharmacologic inhibition of epigenetic modifying enzymes was undertaken in PLD model mice.
RESULTS: Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility during cystogenesis in both male and female PLD cholangiocytes. We identified a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes and showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase slowed cyst growth in male, but not female, PLD mice. In contrast, we found that H3K27ac was specifically increased in female PLD mice and that genes associated with H3K27ac-gained regions were enriched for cyst-related pathways. In an integrated epigenomic and transcriptomic analysis, we identified an estrogen receptor alpha-centered transcription factor network associating with the H3K27ac-regulated cystogenic gene expression program in female PLD mice.
CONCLUSIONS: Our findings highlight multi-layered sex-specific epigenetic dynamics underlying cholangiocyte state transition and identify a potential epigenetic therapeutic strategy for male PLD patients.
LMPACT AND IMPLICATIONS: In the present study, we elucidate a sex-specific epigenetic mechanism underlying the cholangiocyte state transition during hepatic cystogenesis and identify epigenetic drugs effectively slow cyst growth in male PLD mice. These findings underscore the importance of sex difference in the pathogenesis of PLD and may guide researchers and physicians to develop gender-specific personalized approaches for PLD treatment.

Keywords:  Chromatin accessibility; Epigenetics; Histone modifications; Polycystic liver disease; sex difference

DOI:  https://doi.org/10.1016/j.jhep.2022.12.033
Nat Commun. 2023 Jan 24. 14(1): 381

A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene.

Yuandi Gao, Laure Guitton-Sert, Julien Dessapt, Yan Coulombe, Amélie Rodrigue, Larissa Milano, Andréanne Blondeau, Nicolai Balle Larsen, Julien P Duxin, Samer Hussein, Amélie Fradet-Turcotte, Jean-Yves Masson.

Fanconi Anemia (FA) is a rare, genome instability-associated disease characterized by a deficiency in repairing DNA crosslinks, which are known to perturb several cellular processes, including DNA transcription, replication, and repair. Formaldehyde, a by-product of metabolism, is thought to drive FA by generating DNA interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs). However, the impact of formaldehyde on global cellular pathways has not been investigated thoroughly. Herein, using a pangenomic CRISPR-Cas9 screen, we identify EXO1 as a critical regulator of formaldehyde-induced DNA lesions. We show that EXO1 knockout cell lines exhibit formaldehyde sensitivity leading to the accumulation of replicative stress, DNA double-strand breaks, and quadriradial chromosomes, a typical feature of FA. After formaldehyde exposure, EXO1 is recruited to chromatin, protects DNA replication forks from degradation, and functions in parallel with the FA pathway to promote cell survival. In vitro, EXO1-mediated exonuclease activity is proficient in removing DPCs. Collectively, we show that EXO1 limits replication stress and DNA damage to counteract formaldehyde-induced genome instability.

DOI: https://doi.org/10.1038/s41467-023-35802-y
Commun Biol. 2023 Jan 27. 6(1): 111

MME+ fibro-adipogenic progenitors are the dominant adipogenic population during fatty infiltration in human skeletal muscle.

Gillian Fitzgerald, Guillermo Turiel, Tatiane Gorski, Inés Soro-Arnaiz, Jing Zhang, Nicola C Casartelli, Evi Masschelein, Nicola A Maffiuletti, Reto Sutter, Michael Leunig, Jean Farup, Katrien De Bock.

Fatty infiltration, the ectopic deposition of adipose tissue within skeletal muscle, is mediated via the adipogenic differentiation of fibro-adipogenic progenitors (FAPs). We used single-nuclei and single-cell RNA sequencing to characterize FAP heterogeneity in patients with fatty infiltration. We identified an MME+ FAP subpopulation which, based on ex vivo characterization as well as transplantation experiments, exhibits high adipogenic potential. MME+ FAPs are characterized by low activity of WNT, known to control adipogenic commitment, and are refractory to the inhibitory role of WNT activators. Using preclinical models for muscle damage versus fatty infiltration, we show that many MME+ FAPs undergo apoptosis during muscle regeneration and differentiate into adipocytes under pathological conditions, leading to a reduction in their abundance. Finally, we utilized the varying fat infiltration levels in human hip muscles and found less MME+ FAPs in fatty infiltrated human muscle. Altogether, we have identified the dominant adipogenic FAP subpopulation in skeletal muscle.

DOI: https://doi.org/10.1038/s42003-023-04504-y
Commun Biol. 2023 Jan 24. 6(1): 96

The antidiabetic drug metformin aids bacteria in hijacking vitamin B12 from the environment through RcdA.

Luxia Yao, Yihan Wang, Shenlu Qin, Shihao Zhu, Lianfeng Wu.

Years of use of the antidiabetic drug metformin has long been associated with the risk of vitamin B12 (B12) deficiency in type 2 diabetes (T2D) patients, although the underlying mechanisms are unclear. Accumulating evidence has shown that metformin may exert beneficial effects by altering the metabolism of the gut microbiota, but whether it induces human B12 deficiency via modulation of bacterial activity remains poorly understood. Here, we show that both metformin and the other biguanide drug phenformin markedly elevate the accumulation of B12 in E. coli. By functional and genomic analysis, we demonstrate that both biguanides can significantly increase the expression of B12 transporter genes, and depletions of vital ones, such as tonB, nearly completely abolish the drugs' effect on bacterial B12 accumulation. Via high-throughput screens in E. coli and C. elegans, we reveal that the TetR-type transcription factor RcdA is required for biguanide-mediated promotion of B12 accumulation and the expressions of B12 transporter genes in bacteria. Together, our study unveils that the antidiabetic drug metformin helps bacteria gather B12 from the environment by increasing the expressions of B12 transporter genes in an RcdA-dependent manner, which may theoretically reduce the B12 supply to T2D patients taking the drug over time.

DOI: https://doi.org/10.1038/s42003-023-04475-0
Nature. 2023 Jan 20.

How your brain stays on task when sizing someone up.



Keywords:  Human behaviour

DOI:  https://doi.org/10.1038/d41586-023-00135-9
J Cell Biol. 2023 Apr 03. pii: e202205133. [Epub ahead of print]222(4):

Tex2 is required for lysosomal functions at TMEM55-dependent ER membrane contact sites.

Yuanjiao Du, Weiping Chang, Lei Gao, Lin Deng, Wei-Ke Ji.

ER tubules form and maintain membrane contact sites (MCSs) with late endosomes/lysosomes (LE/lys). The molecular composition and cellular functions of these MCSs are poorly understood. Here, we find that Tex2, an SMP domain-containing lipid transfer protein conserved in metazoan and yeast, is a tubular ER protein and is recruited to ER-LE/lys MCSs by TMEM55, phosphatases that convert PI(4,5)P2 to PI5P on LE/lys. We show that the Tex2-TMEM55 interaction occurs between an N-terminal region of Tex2 and a catalytic motif in the PTase domain of TMEM55. The Tex2-TMEM55 interaction can be regulated by endosome-resident type 2 PI4K activities. Functionally, Tex2 knockout results in defects in lysosomal trafficking, digestive capacity, and lipid composition of LE/lys membranes. Together, our data identify Tex2 as a tubular ER protein that resides at TMEM55-dependent ER-LE/lys MCSs required for lysosomal functions.

DOI: https://doi.org/10.1083/jcb.202205133
Nature. 2023 Jan 27.

Flu, MERS and Ebola - the disease outbreaks most frequently reported.

Sara Reardon.



Keywords:  Diseases; Public health

DOI:  https://doi.org/10.1038/d41586-023-00196-w
J Immunol. 2023 Jan 25. pii: ji2200746. [Epub ahead of print]

IFN-Induced Protein with Tetratricopeptide Repeats 2 Limits Autoimmune Inflammation by Regulating Myeloid Cell Activation and Metabolic Activity.

Dongkyun Kim, Nagendra Kumar Rai, Amy Burrows, Sohee Kim, Ajai Tripathi, Samuel E Weinberg, Ranjan Dutta, Ganes C Sen, Booki Min.

Besides antiviral functions, type I IFN expresses potent anti-inflammatory properties and is being widely used to treat certain autoimmune conditions, such as multiple sclerosis. In a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, administration of IFN-β effectively attenuates the disease development. However, the precise mechanisms underlying IFN-β-mediated treatment remain elusive. In this study, we report that IFN-induced protein with tetratricopeptide repeats 2 (Ifit2), a type I and type III IFN-stimulated gene, plays a previously unrecognized immune-regulatory role during autoimmune neuroinflammation. Mice deficient in Ifit2 displayed greater susceptibility to experimental autoimmune encephalomyelitis and escalated immune cell infiltration in the CNS. Ifit2 deficiency was also associated with microglial activation and increased myeloid cell infiltration. We also observed that myelin debris clearance and the subsequent remyelination were substantially impaired in Ifit2-/- CNS tissues. Clearing myelin debris is an important function of the reparative-type myeloid cell subset to promote remyelination. Indeed, we observed that bone marrow-derived macrophages, CNS-infiltrating myeloid cells, and microglia from Ifit2-/- mice express cytokine and metabolic genes associated with proinflammatory-type myeloid cell subsets. Taken together, our findings uncover a novel regulatory function of Ifit2 in autoimmune inflammation in part by modulating myeloid cell function and metabolic activity.

DOI: https://doi.org/10.4049/jimmunol.2200746
Lab Anim (NY). 2023 Jan 25.

Human NK cells control HIV infection in a mouse model.

Charlotte Harrison.

DOI: https://doi.org/10.1038/s41684-023-01121-4
Commun Biol. 2023 Jan 24. 6(1): 97

Murine breast cancers disorganize the liver transcriptome in a zonated manner.

Alexis Vandenbon, Rin Mizuno, Riyo Konishi, Masaya Onishi, Kyoko Masuda, Yuka Kobayashi, Hiroshi Kawamoto, Ayako Suzuki, Chenfeng He, Yuki Nakamura, Kosuke Kawaguchi, Masakazu Toi, Masahito Shimizu, Yasuhito Tanaka, Yutaka Suzuki, Shinpei Kawaoka.

The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver.

DOI: https://doi.org/10.1038/s42003-023-04479-w
Nat Commun. 2023 Jan 27. 14(1): 453

Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain.

Shelei Pan, Peter H Yang, Dakota DeFreitas, Sruthi Ramagiri, Peter O Bayguinov, Carl D Hacker, Abraham Z Snyder, Jackson Wilborn, Hengbo Huang, Gretchen M Koller, Dhvanii K Raval, Grace L Halupnik, Sanja Sviben, Samuel Achilefu, Rui Tang, Gabriel Haller, James D Quirk, James A J Fitzpatrick, Prabagaran Esakky, Jennifer M Strahle.

Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate CSF-parenchymal interactions involving 24 functional-anatomic cell groupings in the brain and spinal cord. CSF distribution to these areas is largely restricted to early development and is altered in posthemorrhagic hydrocephalus. Our study also presents particle size-dependent CSF circulation patterns through the CNS including interaction between neurons and small CSF tracers, but not large CSF tracers. These findings have implications for understanding the biological basis of normal brain development and the pathogenesis of a broad range of disease states, including hydrocephalus.

DOI: https://doi.org/10.1038/s41467-023-36083-1
Trends Endocrinol Metab. 2023 Jan 19. pii: S1043-2760(23)00014-0. [Epub ahead of print]

Metabolism, homeostasis, and aging.

Alibek Moldakozhayev, Vadim N Gladyshev.

  We propose a two-mode (pursuit/maintenance) model of metabolism defined by usable resource availability. Pursuit, consisting of anabolism and catabolism, dominates when usable resources are plentiful and leads to the generation of metabolic waste. In turn, maintenance of a system is activated by elevated metabolic waste during resource depletion. Interaction with the environment results in pendulum-like swings between these metabolic states in thriveless attempts to maintain the least deleterious organismal state - ephemeral homeostasis. Imperfectness of biological processes during these attempts supports the accumulation of the deleteriome, driving organismal aging. We discuss how metabolic adjustment by the environment and resource stabilization may modulate healthspan and lifespan.

Keywords:  aging; homeostasis; maintenance; metabolism; pursuit

DOI:  https://doi.org/10.1016/j.tem.2023.01.003
Nat Commun. 2023 Jan 25. 14(1): 312

A FRET-based respirasome assembly screen identifies spleen tyrosine kinase as a target to improve muscle mitochondrial respiration and exercise performance in mice.

Ami Kobayashi, Kotaro Azuma, Toshihiko Takeiwa, Toshimori Kitami, Kuniko Horie, Kazuhiro Ikeda, Satoshi Inoue.

Aerobic muscle activities predominantly depend on fuel energy supply by mitochondrial respiration, thus, mitochondrial activity enhancement may become a therapeutic intervention for muscle disturbances. The assembly of mitochondrial respiratory complexes into higher-order "supercomplex" structures has been proposed to be an efficient biological process for energy synthesis, although there is controversy in its physiological relevance. We here established Förster resonance energy transfer (FRET) phenomenon-based live imaging of mitochondrial respiratory complexes I and IV interactions using murine myoblastic cells, whose signals represent in vivo supercomplex assembly of complexes I, III, and IV, or respirasomes. The live FRET signals were well correlated with supercomplex assembly observed by blue native polyacrylamide gel electrophoresis (BN-PAGE) and oxygen consumption rates. FRET-based live cell screen defined that the inhibition of spleen tyrosine kinase (SYK), a non-receptor protein tyrosine kinase that belongs to the SYK/ zeta-chain-associated protein kinase 70 (ZAP-70) family, leads to an increase in supercomplex assembly in murine myoblastic cells. In parallel, SYK inhibition enhanced mitochondrial respiration in the cells. Notably, SYK inhibitor administration enhances exercise performance in mice. Overall, this study proves the feasibility of FRET-based respirasome assembly assay, which recapitulates in vivo mitochondrial respiration activities.

DOI: https://doi.org/10.1038/s41467-023-35865-x
Dev Cell. 2023 Jan 23. pii: S1534-5807(22)00875-9. [Epub ahead of print]58(2): 94-109.e6

A cellular hierarchy of Notch and Kras signaling controls cell fate specification in the developing mouse salivary gland.

Lemonia Chatzeli, Ignacio Bordeu, Seungmin Han, Sara Bisetto, Zahra Waheed, Bon-Kyoung Koo, Maria P Alcolea, Benjamin D Simons.

  The development of the mouse salivary gland involves a tip-driven process of branching morphogenesis that takes place in concert with differentiation into acinar, myoepithelial, and ductal (basal and luminal) sub-lineages. By combining clonal lineage tracing with a three-dimensional (3D) reconstruction of the branched epithelial network and single-cell RNA-seq analysis, we show that in tips, a heterogeneous population of renewing progenitors transition from a Krt14+ multipotent state to unipotent states via two transcriptionally distinct bipotent states, one restricted to the Krt14+ basal and myoepithelial lineage and the other to the Krt8+ acinar and luminal lineage. Using genetic perturbations, we show how the differential expression of Notch signaling correlates with spatial segregation, exits from multipotency, and promotes the Krt8+ lineage, whereas Kras activation promotes proacinar fate. These findings provide a mechanistic basis for how positional cues within growing tips regulate the process of lineage segregation and ductal patterning.

Keywords:  Kras; Krt14; Notch; acini; branching; development; differentiation; duct; potency; salivary gland

DOI:  https://doi.org/10.1016/j.devcel.2022.12.009