bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–09–01
28 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration.
  2. Debate rages over Alzheimer's drug lecanemab as UK limits approval.
  3. PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.
  4. RNA polymerases reshape chromatin architecture and couple transcription on individual fibers.
  5. The hidden strength of CD8+ T cells in chronic hepatitis B.
  6. OLAH connects fatty acid metabolism to the severity of respiratory viral disease.
  7. A brief guide to studying extracellular vesicle function in the context of metabolism.
  8. Daily briefing: We age in spurts at 44 and 60 years old.
  9. Maternal Helminth Infection Causes Dysfunctional B Cell Development in Male Offspring.
  10. Identification of inflammatory lipid-associated macrophages in human carotid atherosclerosis.
  11. Fate induction in CD8 CAR T cells through asymmetric cell division.
  12. Systems immunology approach for targeting inflammation in atherosclerosis.
  13. Exclusive: the papers that most heavily cite retracted studies.
  14. Lactate helps cancer cells resist chemotherapy.
  15. RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment.
  16. A deeper dive into amyloid clearance by meningeal lymphatic vessels.
  17. Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
  18. What Science and Nature are good for: causing paper cuts.
  19. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
  20. Ubiquitin gets sweet: Sugar-mediated ubiquitination regulates Nrf1 function.
  21. Stroke alters the innate immune memory and drives inflammatory cardiac dysfunction.
  22. Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.
  23. Spatially clustered type I interferon responses at injury borderzones.
  24. Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
  25. P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
  26. Animal and bacterial viruses share conserved mechanisms of immune evasion.
  27. Identifying the sensor elements of regulatory T cells in atherosclerosis.
  28. Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank.
  1. Cell. 2024 Aug 19. pii: S0092-8674(24)00835-3. [Epub ahead of print]
    Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration.
    Daniel R Hochbaum, Lauren Hulshof, Amanda Urke, Wengang Wang, Alexandra C Dubinsky, Hannah C Farnsworth, Richard Hakim, Sherry Lin, Giona Kleinberg, Keiramarie Robertson, Canaria Park, Alyssa Solberg, Yechan Yang, Caroline Baynard, Naeem M Nadaf, Celia C Beron, Allison E Girasole, Lynne Chantranupong, Marissa D Cortopassi, Shannon Prouty, Ludwig Geistlinger, Alexander S Banks, Thomas S Scanlan, Sandeep Robert Datta, Michael E Greenberg, Gabriella L Boulting, Evan Z Macosko, Bernardo L Sabatini.
      Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone-a regulator of metabolism in many peripheral organs-directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.
    Keywords:  body-brain coordination; exploration; metabolism; neuroscience; synaptic plasticity; thyroid hormone; transcriptionally regulated behavior
    DOI:  https://doi.org/10.1016/j.cell.2024.07.041
  2. Nature. 2024 Aug 22.
    Debate rages over Alzheimer's drug lecanemab as UK limits approval.
    Diana Kwon.
      
    Keywords:  Alzheimer's disease; Drug discovery; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02720-y
  3. Nat Commun. 2024 Aug 24. 15(1): 7303
    PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.
    Priya Mittal, Jacquelyn A Myers, Raymond D Carter, Sandi Radko-Juettner, Hayden A Malone, Wojciech Rosikiewicz, Alexis N Robertson, Zhexin Zhu, Ishwarya V Narayanan, Baranda S Hansen, Meadow Parrish, Natarajan V Bhanu, Robert J Mobley, Jerold E Rehg, Beisi Xu, Yiannis Drosos, Shondra M Pruett-Miller, Mats Ljungman, Benjamin A Garcia, Gang Wu, Janet F Partridge, Charles W M Roberts.
      Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.
    DOI:  https://doi.org/10.1038/s41467-024-51566-5
  4. Mol Cell. 2024 Aug 23. pii: S1097-2765(24)00667-1. [Epub ahead of print]
    RNA polymerases reshape chromatin architecture and couple transcription on individual fibers.
    Thomas W Tullius, R Stefan Isaac, Danilo Dubocanin, Jane Ranchalis, L Stirling Churchman, Andrew B Stergachis.
      RNA polymerases must initiate and pause within a complex chromatin environment, surrounded by nucleosomes and other transcriptional machinery. This environment creates a spatial arrangement along individual chromatin fibers ripe for both competition and coordination, yet these relationships remain largely unknown owing to the inherent limitations of traditional structural and sequencing methodologies. To address this, we employed long-read chromatin fiber sequencing (Fiber-seq) in Drosophila to visualize RNA polymerase (Pol) within its native chromatin context with single-molecule precision along up to 30 kb fibers. We demonstrate that Fiber-seq enables the identification of individual Pol II, nucleosome, and transcription factor footprints, revealing Pol II pausing-driven destabilization of downstream nucleosomes. Furthermore, we demonstrate pervasive direct distance-dependent transcriptional coupling between nearby Pol II genes, Pol III genes, and transcribed enhancers, modulated by local chromatin architecture. Overall, transcription initiation reshapes surrounding nucleosome architecture and couples nearby transcriptional machinery along individual chromatin fibers.
    Keywords:  Fiber-seq; RNA Pol II; RNA Pol III; chromatin; nucleosome; promoter proximal pausing; single-molecule; transcription initiation
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.013
  5. Nat Immunol. 2024 Sep;25(9): 1515-1516
    The hidden strength of CD8+ T cells in chronic hepatitis B.
    Francesco Andreata, Matteo Iannacone.
      
    DOI:  https://doi.org/10.1038/s41590-024-01939-1
  6. Cell. 2024 Aug 22. pii: S0092-8674(24)00826-2. [Epub ahead of print]187(17): 4549-4551
    OLAH connects fatty acid metabolism to the severity of respiratory viral disease.
    Rohan Palanki, Hannah Yamagata, Michael J Mitchell.
      Respiratory virus infections may cause profound respiratory illness, yet the factors that underlie disease severity are not well understood. In this issue of Cell, Jia, Crawford, et al.1 identify the role of oleoyl-ACP-hydrolase (OLAH) in mediating life-threatening inflammation associated with viral respiratory disease severity.
    DOI:  https://doi.org/10.1016/j.cell.2024.07.032
  7. Nat Metab. 2024 Aug 26.
    A brief guide to studying extracellular vesicle function in the context of metabolism.
    Daniel Stephen Lark, Kerstin Stemmer, Wei Ying, Clair Crewe.
      
    DOI:  https://doi.org/10.1038/s42255-024-01112-w
  8. Nature. 2024 Aug 16.
    Daily briefing: We age in spurts at 44 and 60 years old.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02707-9
  9. J Immunol. 2024 Aug 26. pii: ji2400158. [Epub ahead of print]
    Maternal Helminth Infection Causes Dysfunctional B Cell Development in Male Offspring.
    Lisa C Gibbs, Juan M Oviedo, Bartholomew N Ondigo, Keke C Fairfax.
      Infections during pregnancy are known to trigger alterations in offspring immunity, often leading to increased disease susceptibility. Maternal helminth infections correlate with lower Ab titers to certain childhood immunizations and putative decreased vaccine efficacy. The mechanisms that underlie how maternal infection blunts offspring humoral responses are unclear. Using our murine model of maternal schistosomiasis, we found that maternal helminth infection decreases the germinal center response of all offspring to tetanus immunization. However, only male offspring have defects in memory B cell and long-lived plasma cell generation. We found this sex-specific aberration begins during B cell development within the bone marrow via alteration of the IL-7 niche and persists throughout antigenic activation in the germinal center in the periphery. Critically, these defects in males are cell intrinsic, persisting following adoptive transfer to control male pups. Together, these data show that maternal infections can alter both the bone marrow microenvironment and the development of B lymphocytes in a sex-specific manner. This study correlates maternal infection induced defects in early life B cell development with ineffective Ab responses after vaccination.
    DOI:  https://doi.org/10.4049/jimmunol.2400158
  10. Nat Cardiovasc Res. 2023 Jul;2(7): 604-605
    Identification of inflammatory lipid-associated macrophages in human carotid atherosclerosis.
    Kory Lavine.
      
    DOI:  https://doi.org/10.1038/s44161-023-00299-7
  11. Nature. 2024 Aug 28.
    Fate induction in CD8 CAR T cells through asymmetric cell division.
    Casey S Lee, Sisi Chen, Corbett T Berry, Andre R Kelly, Patrick J Herman, Sangwook Oh, Roddy S O'Connor, Aimee S Payne, Christoph T Ellebrecht.
      Early expansion and long-term persistence predict efficacy of chimeric antigen receptor T cells (CARTs)1-7, but mechanisms governing effector versus memory CART differentiation and whether asymmetric cell division induces differential fates in human CARTs remain unclear. Here we show that target-induced proximity labelling enables isolation of first-division proximal-daughter and distal-daughter CD8 CARTs that asymmetrically distribute their surface proteome and transcriptome, resulting in divergent fates. Target-engaged CARs remain on proximal daughters, which inherit a surface proteome resembling activated-undivided CARTs, whereas the endogenous T cell receptor and CD8 enrich on distal daughters, whose surface proteome resembles resting CARTs, correlating with glycolytic and oxidative metabolism, respectively. Despite memory-precursor phenotype and in vivo longevity, distal daughters demonstrate transient potent cytolytic activity similar to proximal daughters, uncovering an effector-like state in distal daughters destined to become memory CARTs. Both partitioning of pre-existing transcripts and changes in RNA velocity contribute to asymmetry of fate-determining factors, resulting in diametrically opposed transcriptional trajectories. Independent of naive, memory or effector surface immunophenotype, proximal-daughter CARTs use core sets of transcription factors known to support proliferation and effector function. Conversely, transcription factors enriched in distal daughters restrain differentiation and promote longevity, evidenced by diminished long-term in vivo persistence and function of distal-daughter CARTs after IKZF1 disruption. These studies establish asymmetric cell division as a framework for understanding mechanisms of CART differentiation and improving therapeutic outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-07862-7
  12. Nat Cardiovasc Res. 2023 Jun;2(6): 500-501
    Systems immunology approach for targeting inflammation in atherosclerosis.
      
    DOI:  https://doi.org/10.1038/s44161-023-00286-y
  13. Nature. 2024 Aug 28.
    Exclusive: the papers that most heavily cite retracted studies.
    Richard Van Noorden, Miryam Naddaf.
      
    Keywords:  Peer review; Publishing
    DOI:  https://doi.org/10.1038/d41586-024-02719-5
  14. Nature. 2024 Aug 23.
    Lactate helps cancer cells resist chemotherapy.
      
    Keywords:  Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02731-9
  15. Nat Commun. 2024 Aug 27. 15(1): 7263
    RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment.
    Xinzhu Shan, Zhiqiang Zhao, Pingping Lai, Yuxiu Liu, Buyao Li, Yubin Ke, Hanqiu Jiang, Yilong Zhou, Wenzhe Li, Qian Wang, Pengxia Qin, Yizhe Xue, Zihan Zhang, Chenlong Wei, Bin Ma, Wei Liu, Cong Luo, Xueguang Lu, Jiaqi Lin, Li Shu, Yin Jie, Xunde Xian, Derfogail Delcassian, Yifan Ge, Lei Miao.
      Metabolic dysfunction-associated steatohepatitis (MASH) poses challenges for targeted delivery and retention of therapeutic proteins due to excess extracellular matrix (ECM). Here we present a new approach to treat MASH, termed "Fibrosis overexpression and retention (FORT)". In this strategy, we design (1) retinoid-derivative lipid nanoparticle (LNP) to enable enhanced mRNA overexpression in fibrotic regions, and (2) mRNA modifications which facilitate anchoring of therapeutic proteins in ECM. LNPs containing carboxyl-retinoids, rather than alcohol- or ester-retinoids, effectively deliver mRNA with over 10-fold enhancement of protein expression in fibrotic livers. The carboxyl-retinoid rearrangement on the LNP surface improves protein binding and membrane fusion. Therapeutic proteins are then engineered with an endogenous collagen-binding domain. These fusion proteins exhibit increased retention in fibrotic lesions and reduced systemic toxicity. In vivo, fibrosis-targeting LNPs encoding fusion proteins demonstrate superior therapeutic efficacy in three clinically relevant male-animal MASH models. This approach holds promise in fibrotic diseases unsuited for protein injection.
    DOI:  https://doi.org/10.1038/s41467-024-51571-8
  16. Nat Cardiovasc Res. 2024 Apr;3(4): 407-409
    A deeper dive into amyloid clearance by meningeal lymphatic vessels.
    Monica M Santisteban, Costantino Iadecola.
      
    DOI:  https://doi.org/10.1038/s44161-024-00427-x
  17. Nat Commun. 2024 Aug 26. 15(1): 7337
    Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
    Niranjana Natarajan, Jonathan Florentin, Ebin Johny, Hanxi Xiao, Scott Patrick O'Neil, Liqun Lei, Jixing Shen, Lee Ohayon, Aaron R Johnson, Krithika Rao, Xiaoyun Li, Yanwu Zhao, Yingze Zhang, Sina Tavakoli, Sruti Shiva, Jishnu Das, Partha Dutta.
      There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
    DOI:  https://doi.org/10.1038/s41467-024-51780-1
  18. Nature. 2024 Aug 23.
    What Science and Nature are good for: causing paper cuts.
      
    Keywords:  Physics
    DOI:  https://doi.org/10.1038/d41586-024-02297-6
  19. Nat Commun. 2024 Aug 27. 15(1): 7378
    Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
    Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.
      The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51363-0
  20. Mol Cell. 2024 Aug 22. pii: S1097-2765(24)00621-X. [Epub ahead of print]84(16): 3003-3005
    Ubiquitin gets sweet: Sugar-mediated ubiquitination regulates Nrf1 function.
    Alison C Mody, Christina M Woo.
      In this issue of Molecular Cell, Yoshida et al.1 report an unconventional sugar-dependent ubiquitination event on Nrf1 that disrupts Nrf1 transcriptional activation.
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.023
  21. Nat Cardiovasc Res. 2024 Aug;3(8): 887
    Stroke alters the innate immune memory and drives inflammatory cardiac dysfunction.
    Gerburg Schwaerzer.
      
    DOI:  https://doi.org/10.1038/s44161-024-00526-9
  22. Nat Cardiovasc Res. 2023 Sep;2(9): 805-818
    Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.
    Philipp J Rauch, Jayakrishnan Gopakumar, Alexander J Silver, Daniel Nachun, Herra Ahmad, Marie McConkey, Tetsushi Nakao, Marc Bosse, Thiago Rentz, Nora Vivanco Gonzalez, Noah F Greenwald, Erin F McCaffrey, Zumana Khair, Manu Gopakumar, Kameron B Rodrigues, Amy E Lin, Eti Sinha, Maia Fefer, Drew N Cohen, Amélie Vromman, Eugenia Shvartz, Galina Sukhova, Sean Bendall, Michael Angelo, Peter Libby, Benjamin L Ebert, Siddhartha Jaiswal.
      Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.
    DOI:  https://doi.org/10.1038/s44161-023-00326-7
  23. Nature. 2024 Aug 28.
    Spatially clustered type I interferon responses at injury borderzones.
    V K Ninh, D M Calcagno, J D Yu, B Zhang, N Taghdiri, R Sehgal, J M Mesfin, C J Chen, K Kalhor, A Toomu, J M Duran, E Adler, J Hu, K Zhang, K L Christman, Z Fu, B Bintu, K R King.
      Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.
    DOI:  https://doi.org/10.1038/s41586-024-07806-1
  24. Nat Commun. 2024 Aug 27. 15(1): 7352
    Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
    William A Hofstadter, Katelyn C Cook, Elene Tsopurashvili, Robert Gebauer, Vojtěch Pražák, Emily A Machala, Ji Woo Park, Kay Grünewald, Emmanuelle R J Quemin, Ileana M Cristea.
      The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51680-4
  25. Nat Commun. 2024 Aug 28. 15(1): 7458
    P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
    Xiangli Jiang, Ali Hyder Baig, Giuliana Palazzo, Rossella Del Pizzo, Toman Bortecen, Sven Groessl, Esther A Zaal, Cinthia Claudia Amaya Ramirez, Alexander Kowar, Daniela Aviles-Huerta, Celia R Berkers, Wilhelm Palm, Darjus Tschaharganeh, Jeroen Krijgsveld, Fabricio Loayza-Puch.
      Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.
    DOI:  https://doi.org/10.1038/s41467-024-51901-w
  26. Cell. 2024 Aug 23. pii: S0092-8674(24)00889-4. [Epub ahead of print]
    Animal and bacterial viruses share conserved mechanisms of immune evasion.
    Samuel J Hobbs, Jason Nomburg, Jennifer A Doudna, Philip J Kranzusch.
      Animal and bacterial cells sense and defend against viral infections using evolutionarily conserved antiviral signaling pathways. Here, we show that viruses overcome host signaling using mechanisms of immune evasion that are directly shared across the eukaryotic and prokaryotic kingdoms of life. Structures of animal poxvirus proteins that inhibit host cGAS-STING signaling demonstrate architectural and catalytic active-site homology shared with bacteriophage Acb1 proteins, which inactivate CBASS anti-phage defense. In bacteria, phage Acb1 proteins are viral enzymes that degrade host cyclic nucleotide immune signals. Structural comparisons of poxvirus protein-2'3'-cGAMP and phage Acb1-3'3'-cGAMP complexes reveal a universal mechanism of host nucleotide immune signal degradation and explain kingdom-specific additions that enable viral adaptation. Chimeric bacteriophages confirm that animal poxvirus proteins are sufficient to evade immune signaling in bacteria. Our findings identify a mechanism of immune evasion conserved between animal and bacterial viruses and define shared rules that explain host-virus interactions across multiple kingdoms of life.
    Keywords:  CBASS; antiviral immunity; cGAS; cGLR; cyclic nucleotide; immune evasion; poxvirus
    DOI:  https://doi.org/10.1016/j.cell.2024.07.057
  27. Nat Cardiovasc Res. 2024 Feb;3(2): 106-107
    Identifying the sensor elements of regulatory T cells in atherosclerosis.
    Dimitrios Tsiantoulas, Christoph J Binder.
      
    DOI:  https://doi.org/10.1038/s44161-023-00416-6
  28. Nat Commun. 2024 Aug 26. 15(1): 7346
    Systematic discovery of gene-environment interactions underlying the human plasma proteome in UK Biobank.
    Biogen Biobank Team
      Understanding how gene-environment interactions (GEIs) influence the circulating proteome could aid in biomarker discovery and validation. The presence of GEIs can be inferred from single nucleotide polymorphisms that associate with phenotypic variability - termed variance quantitative trait loci (vQTLs). Here, vQTL association studies are performed on plasma levels of 1463 proteins in 52,363 UK Biobank participants. A set of 677 independent vQTLs are identified across 568 proteins. They include 67 variants that lack conventional additive main effects on protein levels. Over 1100 GEIs are identified between 101 proteins and 153 environmental exposures. GEI analyses uncover possible mechanisms that explain why 13/67 vQTL-only sites lack corresponding main effects. Additional analyses also highlight how age, sex, epistatic interactions and statistical artefacts may underscore associations between genetic variation and variance heterogeneity. This study establishes the most comprehensive database yet of vQTLs and GEIs for the human proteome.
    DOI:  https://doi.org/10.1038/s41467-024-51744-5
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