bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–12–10
23 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Organ aging signatures in the plasma proteome track health and disease.
  2. JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer's disease.
  3. Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
  4. Blazed oblique plane microscopy reveals scale-invariant inference of brain-wide population activity.
  5. Assembly mechanism of the inflammasome sensor AIM2 revealed by single molecule analysis.
  6. Adipose tissue maintains healthy joint fibroblasts via cortisol signalling.
  7. Dictionary of immune responses to cytokines at single-cell resolution.
  8. A neuronal coping mechanism linking stress-induced anxiety to motivation for reward.
  9. Isoleucine dietary restriction boosts healthspan and longevity in mice.
  10. mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
  11. Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.
  12. Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila.
  13. Integration of genetic data with dynamic gene regulatory elements identifies autoimmune effector cell states.
  14. Dynamic encounters with red blood cells trigger splenic marginal zone B cell retention and function.
  15. Metabolically regulated lineages in prostate cancer.
  16. Genetic risk converges on regulatory networks mediating early type 2 diabetes.
  17. A reversible epigenetic memory of inflammatory injury controls lineage plasticity and tumor initiation in the mouse pancreas.
  18. TCRs and AI: the future is now.
  19. Neonatal monocytes suppress adult TH17 cell responses in skin.
  20. Periportal hepatocyte proliferation at midgestation governs maternal glucose homeostasis in mice.
  21. The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.
  22. Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
  23. A genomic mutational constraint map using variation in 76,156 human genomes.
  1. Nature. 2023 Dec;624(7990): 164-172
    Organ aging signatures in the plasma proteome track health and disease.
    Hamilton Se-Hwee Oh, Jarod Rutledge, Daniel Nachun, Róbert Pálovics, Olamide Abiose, Patricia Moran-Losada, Divya Channappa, Deniz Yagmur Urey, Kate Kim, Yun Ju Sung, Lihua Wang, Jigyasha Timsina, Dan Western, Menghan Liu, Pat Kohlfeld, John Budde, Edward N Wilson, Yann Guen, Taylor M Maurer, Michael Haney, Andrew C Yang, Zihuai He, Michael D Greicius, Katrin I Andreasson, Sanish Sathyan, Erica F Weiss, Sofiya Milman, Nir Barzilai, Carlos Cruchaga, Anthony D Wagner, Elizabeth Mormino, Benoit Lehallier, Victor W Henderson, Frank M Longo, Stephen B Montgomery, Tony Wyss-Coray.
      Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.
    DOI:  https://doi.org/10.1038/s41586-023-06802-1
  2. Nat Commun. 2023 Dec 04. 14(1): 8021
    JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer's disease.
    Chiara Scopa, Samantha M Barnada, Maria E Cicardi, Mo Singer, Davide Trotti, Marco Trizzino.
      Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.
    DOI:  https://doi.org/10.1038/s41467-023-43728-8
  3. Sci Adv. 2023 Dec 08. 9(49): eadf9522
    Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
    Chao Chen, Hong Zheng, Edwin M Horwitz, Satomi Ando, Koichi Araki, Peng Zhao, Zhiguo Li, Mandy L Ford, Rafi Ahmed, Cheng-Kui Qu.
      Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.adf9522
  4. Nat Commun. 2023 Dec 04. 14(1): 8019
    Blazed oblique plane microscopy reveals scale-invariant inference of brain-wide population activity.
    Maximilian Hoffmann, Jörg Henninger, Johannes Veith, Lars Richter, Benjamin Judkewitz.
      Due to the size and opacity of vertebrate brains, it has until now been impossible to simultaneously record neuronal activity at cellular resolution across the entire adult brain. As a result, scientists are forced to choose between cellular-resolution microscopy over limited fields-of-view or whole-brain imaging at coarse-grained resolution. Bridging the gap between these spatial scales of understanding remains a major challenge in neuroscience. Here, we introduce blazed oblique plane microscopy to perform brain-wide recording of neuronal activity at cellular resolution in an adult vertebrate. Contrary to common belief, we find that inferences of neuronal population activity are near-independent of spatial scale: a set of randomly sampled neurons has a comparable predictive power as the same number of coarse-grained macrovoxels. Our work thus links cellular resolution with brain-wide scope, challenges the prevailing view that macroscale methods are generally inferior to microscale techniques and underscores the value of multiscale approaches to studying brain-wide activity.
    DOI:  https://doi.org/10.1038/s41467-023-43741-x
  5. Nat Commun. 2023 Dec 02. 14(1): 7957
    Assembly mechanism of the inflammasome sensor AIM2 revealed by single molecule analysis.
    Meenakshi Sharma, Eva de Alba.
      Pathogenic dsDNA prompts AIM2 assembly leading to the formation of the inflammasome, a multimeric complex that triggers the inflammatory response. The recognition of foreign dsDNA involves AIM2 self-assembly concomitant with dsDNA binding. However, we lack mechanistic and kinetic information on the formation and propagation of the assembly, which can shed light on innate immunity's time response and specificity. Combining optical traps and confocal fluorescence microscopy, we determine here the association and dissociation rates of the AIM2-DNA complex at the single molecule level. We identify distinct mechanisms for oligomer growth via the binding of incoming AIM2 molecules to adjacent dsDNA or direct interaction with bound AIM2 assemblies, resembling primary and secondary nucleation. Through these mechanisms, the size of AIM2 oligomers can increase fourfold in seconds. Finally, our data indicate that single AIM2 molecules do not diffuse/scan along the DNA, suggesting that oligomerization depends on stochastic encounters with DNA and/or DNA-bound AIM2.
    DOI:  https://doi.org/10.1038/s41467-023-43691-4
  6. Nat Rev Immunol. 2023 Dec 06.
    Adipose tissue maintains healthy joint fibroblasts via cortisol signalling.
    Micon Garvilles, Mark Coles.
      
    DOI:  https://doi.org/10.1038/s41577-023-00977-4
  7. Nature. 2023 Dec 06.
    Dictionary of immune responses to cytokines at single-cell resolution.
    Ang Cui, Teddy Huang, Shuqiang Li, Aileen Ma, Jorge L Pérez, Chris Sander, Derin B Keskin, Catherine J Wu, Ernest Fraenkel, Nir Hacohen.
      Cytokines mediate cell-cell communication in the immune system and represent important therapeutic targets1-3. A myriad of studies have highlighted their central role in immune function4-13, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine-cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1β induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell-cell communication networks in any immune response.
    DOI:  https://doi.org/10.1038/s41586-023-06816-9
  8. Sci Adv. 2023 Dec 08. 9(49): eadh9620
    A neuronal coping mechanism linking stress-induced anxiety to motivation for reward.
    Paul M Klenowski, Rubing Zhao-Shea, Timothy G Freels, Susanna Molas, Max Zinter, Peter M'Angale, Cong Xiao, Leonora Martinez-Núñez, Travis Thomson, Andrew R Tapper.
      Stress coping involves innate and active motivational behaviors that reduce anxiety under stressful situations. However, the neuronal bases directly linking stress, anxiety, and motivation are largely unknown. Here, we show that acute stressors activate mouse GABAergic neurons in the interpeduncular nucleus (IPN). Stress-coping behavior including self-grooming and reward behavior including sucrose consumption inherently reduced IPN GABAergic neuron activity. Optogenetic silencing of IPN GABAergic neuron activation during acute stress episodes mimicked coping strategies and alleviated anxiety-like behavior. In a mouse model of stress-enhanced motivation for sucrose seeking, photoinhibition of IPN GABAergic neurons reduced stress-induced motivation for sucrose, whereas photoactivation of IPN GABAergic neurons or excitatory inputs from medial habenula potentiated sucrose seeking. Single-cell sequencing, fiber photometry, and optogenetic experiments revealed that stress-activated IPN GABAergic neurons that drive motivated sucrose seeking express somatostatin. Together, these data suggest that stress induces innate behaviors and motivates reward seeking to oppose IPN neuronal activation as an anxiolytic stress-coping mechanism.
    DOI:  https://doi.org/10.1126/sciadv.adh9620
  9. Nat Aging. 2023 Dec 06.
    Isoleucine dietary restriction boosts healthspan and longevity in mice.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-023-00547-2
  10. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00417-5. [Epub ahead of print]35(12): 2097-2099
    mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
    Estela Jacinto.
      Nutrient availability is conveyed to the mechanistic target of rapamycin (mTOR), which couples metabolic processes with cell growth and proliferation. How mTOR itself is modulated by amino acid levels remains poorly understood. Ge and colleagues now demonstrate that broad sensing of uncharged tRNAs by GCN2/FBXO22 inactivates mTOR complex 1 (mTORC1) via mTOR ubiquitination.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.006
  11. Nat Commun. 2023 Dec 02. 14(1): 7994
    Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.
    Erik Schoenmakers, Federica Marelli, Helle F Jørgensen, W Edward Visser, Carla Moran, Stefan Groeneweg, Carolina Avalos, Sean J Jurgens, Nichola Figg, Alison Finigan, Neha Wali, Maura Agostini, Hannah Wardle-Jones, Greta Lyons, Rosemary Rusk, Deepa Gopalan, Philip Twiss, Jacob J Visser, Martin Goddard, Samer A M Nashef, Robin Heijmen, Paul Clift, Sanjay Sinha, James P Pirruccello, Patrick T Ellinor, Elisabeth M Busch-Nentwich, Ramiro Ramirez-Solis, Michael P Murphy, Luca Persani, Martin Bennett, Krishna Chatterjee.
      Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.
    DOI:  https://doi.org/10.1038/s41467-023-43851-6
  12. Nat Commun. 2023 Dec 05. 14(1): 7832
    Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila.
    Hina Kosakamoto, Fumiaki Obata, Junpei Kuraishi, Hide Aikawa, Rina Okada, Joshua N Johnstone, Taro Onuma, Matthew D W Piper, Masayuki Miura.
      Methionine restriction (MetR) extends lifespan in various organisms, but its mechanistic understanding remains incomplete. Whether MetR during a specific period of adulthood increases lifespan is not known. In Drosophila, MetR is reported to extend lifespan only when amino acid levels are low. Here, by using an exome-matched holidic medium, we show that decreasing Met levels to 10% extends Drosophila lifespan with or without decreasing total amino acid levels. MetR during the first four weeks of adult life only robustly extends lifespan. MetR in young flies induces the expression of many longevity-related genes, including Methionine sulfoxide reductase A (MsrA), which reduces oxidatively-damaged Met. MsrA induction is foxo-dependent and persists for two weeks after cessation of the MetR diet. Loss of MsrA attenuates lifespan extension by early-adulthood MetR. Our study highlights the age-dependency of the organismal response to specific nutrients and suggests that nutrient restriction during a particular period of life is sufficient for healthspan extension.
    DOI:  https://doi.org/10.1038/s41467-023-43550-2
  13. Nat Genet. 2023 Dec 04.
    Integration of genetic data with dynamic gene regulatory elements identifies autoimmune effector cell states.
      
    DOI:  https://doi.org/10.1038/s41588-023-01578-6
  14. Nat Immunol. 2023 Dec 04.
    Dynamic encounters with red blood cells trigger splenic marginal zone B cell retention and function.
    Dan Liu, Benjamin Y Winer, Marissa Y Chou, Hanson Tam, Ying Xu, Jinping An, James M Gardner, Jason G Cyster.
      Spleen marginal zone (MZ) B cells are important for antibody responses against blood-borne antigens. The signals they use to detect exposure to blood are not well defined. Here, using intravital two-photon microscopy in mice, we observe transient contacts between MZ B cells and red blood cells that are in flow. We show that MZ B cells use adhesion G-protein-coupled receptor ADGRE5 (CD97) for retention in the spleen. CD97 function in MZ B cells depends on its ability to undergo autoproteolytic cleavage and signaling via Gα13 and ARHGEF1. Red blood cell expression of the CD97 ligand CD55 is required for MZ B cell homeostasis. Applying a pulling force on CD97-transfected cells using an optical C-trap and CD55+ beads leads to accumulation of active RhoA and membrane retraction. Finally, we show that CD97 deficiency leads to a reduced T cell-independent IgM response. Thus, our studies provide evidence that MZ B cells use mechanosensing to position in a manner that enhances antibody responses against blood-borne antigens.
    DOI:  https://doi.org/10.1038/s41590-023-01690-z
  15. Nat Cell Biol. 2023 Dec 04.
    Metabolically regulated lineages in prostate cancer.
    Martin K Bakht, Himisha Beltran.
      
    DOI:  https://doi.org/10.1038/s41556-023-01298-3
  16. Nature. 2023 Dec 04.
    Genetic risk converges on regulatory networks mediating early type 2 diabetes.
    HPAP Consortium
      Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3-5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by β cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the β cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by β cells. RFX6 perturbation in primary human islet cells alters β cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.
    DOI:  https://doi.org/10.1038/s41586-023-06693-2
  17. Dev Cell. 2023 Nov 30. pii: S1534-5807(23)00583-X. [Epub ahead of print]
    A reversible epigenetic memory of inflammatory injury controls lineage plasticity and tumor initiation in the mouse pancreas.
    David J Falvo, Adrien Grimont, Paul Zumbo, William B Fall, Julie L Yang, Alexa Osterhoudt, Grace Pan, Andre F Rendeiro, Yinuo Meng, John E Wilkinson, Friederike Dündar, Olivier Elemento, Rhonda K Yantiss, Erika Hissong, Richard Koche, Doron Betel, Rohit Chandwani.
      Inflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.
    Keywords:  ATAC-seq; CUT&TAG; cell fate; epigenetic memory; inflammatory injury; lineage plasticity; pancreatic cancer; pancreatitis; single-cell RNA sequencing; tumorigenesis
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.008
  18. Nat Rev Immunol. 2023 Dec 06.
    TCRs and AI: the future is now.
    Malcolm J W Sim.
      
    DOI:  https://doi.org/10.1038/s41577-023-00974-7
  19. Nat Rev Immunol. 2023 Dec 04.
    Neonatal monocytes suppress adult TH17 cell responses in skin.
    Siu Ling Tai, Arthur Mortha.
      
    DOI:  https://doi.org/10.1038/s41577-023-00975-6
  20. Commun Biol. 2023 Dec 04. 6(1): 1226
    Periportal hepatocyte proliferation at midgestation governs maternal glucose homeostasis in mice.
    Satoshi Kozuki, Mio Kabata, Satoko Sakurai, Keiko Iwaisako, Tomomi Nishimura, Masakazu Toi, Takuya Yamamoto, Fumiko Toyoshima.
      The maternal liver is challenged by metabolic demands throughout pregnancy. However, hepatocyte dynamics and their physiological significance in pregnancy remain unclear. Here, we show in mice that hepatocyte proliferation is spatiotemporally regulated in each liver lobular zone during pregnancy, with transient proliferation of periportal and pericentral hepatocytes during mid and late gestation, respectively. Using adeno-associated virus (AAV)-8-mediated expression of the cell cycle inhibitor p21 in hepatocytes, we show that inhibition of hepatocyte proliferation during mid, but not late, gestation impairs liver growth. Transcriptionally, genes involved in glucose/glycogen metabolism are downregulated in late pregnancy when midgestational hepatocyte proliferation is attenuated. In addition, hepatic glycogen storage is abolished, with concomitant elevated blood glucose concentrations, glucose intolerance, placental glycogen deposition, and fetal overgrowth. Laser capture microdissection and RNA-seq analysis of each liver lobular zone show zone-specific changes in the transcriptome during pregnancy and identify genes that are periportally expressed at midgestation, including the hyaluronan-mediated motility receptor (Hmmr). Knockdown of Hmmr in hepatocytes by AAV8-shHmmr suppresses periportal hepatocyte proliferation at midgestation and induces impaired hepatic glycogen storage, glucose intolerance, placental glycogen deposition and fetal overgrowth. Our results suggest that periportal hepatocyte proliferation during midgestation is critical for maternal glycogen metabolism and fetal size.
    DOI:  https://doi.org/10.1038/s42003-023-05614-3
  21. J Immunol. 2023 Dec 06. pii: ji2200462. [Epub ahead of print]
    The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.
    Zhongxia Yu, Li Tong, Chenkai Ma, Hui Song, Jie Wang, Li Chai, Caiwei Wang, Mengge Wang, Chunying Wang, Rongzhen Yan, Yue Fu, Mutian Jia, Wei Zhao, Chunyuan Zhao.
      Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.
    DOI:  https://doi.org/10.4049/jimmunol.2200462
  22. FEBS Lett. 2023 Dec 06.
    Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
    Francesco De Leonardis, Amer Ahmed, Angelo Vozza, Loredana Capobianco, Christopher L Riley, Simona Nicole Barile, Daria Di Molfetta, Stefano Tiziani, John DiGiovanni, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.
      Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient "uncoupled" respiration, including fasting and exercise. Here we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, oxaloacetate, and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.
    Keywords:  amino acid transport; anion transport; bioenergetics; mitochondrial metabolism; mitochondrial transport; uncoupling protein
    DOI:  https://doi.org/10.1002/1873-3468.14784
  23. Nature. 2023 Dec 06.
    A genomic mutational constraint map using variation in 76,156 human genomes.
    Genome Aggregation Database Consortium
      The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.
    DOI:  https://doi.org/10.1038/s41586-023-06045-0
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