bims-minimp Biomed News
on Mitochondria, innate immunity, proteostasis
Issue of 2021‒06‒27
28 papers selected by
Hanna Salmonowicz
Newcastle University
  1. Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans.
  2. HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue.
  3. Arginine monomethylation by PRMT7 controls MAVS-mediated antiviral innate immunity.
  4. Mitochondrial-derived vesicles compensate for loss of LC3-mediated mitophagy.
  5. Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response.
  6. Mitochondrial metabolism regulates macrophage biology.
  7. The mitochondrial permeability transition pore: an evolving concept critical for cell life and death.
  8. Cellular nucleic acid-binding protein is essential for type I interferon-mediated immunity to RNA virus infection.
  9. Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.
  10. Light-inducible deformation of mitochondria in live cells.
  11. Expression of LONP1 Is High in Visceral Adipose Tissue in Obesity, and Is Associated with Glucose and Lipid Metabolism.
  12. DHX15 is required to control RNA virus-induced intestinal inflammation.
  13. Gut microbiota mediate the FGF21 adaptive stress response to chronic dietary protein-restriction in mice.
  14. GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.
  15. TAK1 inhibition elicits mitochondrial ROS to block intracellular bacterial colonization.
  16. Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation.
  17. BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy.
  18. Intracellular H2S production is an autophagy-dependent adaptive response to DNA damage.
  19. mTORC1 Activation is Not Sufficient to Suppress Hepatic PPARα Signaling or Ketogenesis.
  20. Blood Mitochondrial DNA Copy Number: What Are We Counting?
  21. N-glycan processing selects ERAD-resistant misfolded proteins for ER-to-lysosome-associated degradation.
  22. Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.
  23. Real-time imaging of viscosity in the mitochondrial matrix by a red-emissive molecular rotor.
  24. The DNA Sensor IFIX Drives Proteome Alterations To Mobilize Nuclear and Cytoplasmic Antiviral Responses, with Its Acetylation Acting as a Localization Toggle.
  25. Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome.
  26. Western diet leads to aging-related tumorigenesis via activation of the inflammatory, UPR, and EMT pathways.
  27. Rhinovirus Reduces the Severity of Subsequent Respiratory Viral Infections by Interferon-Dependent and -Independent Mechanisms.
  28. Sex-Related Overactivation of NLRP3 Inflammasome Increases Lethality of the Male COVID-19 Patients.
  1. Sci Adv. 2021 Jun;pii: eabg3012. [Epub ahead of print]7(26):
    Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans.
    Giuseppe Calculli, Hyun Ju Lee, Koning Shen, Uyen Pham, Marija Herholz, Aleksandra Trifunovic, Andrew Dillin, David Vilchez.
      Protein aggregation causes intracellular changes in neurons, which elicit signals to modulate proteostasis in the periphery. Beyond the nervous system, a fundamental question is whether other organs also communicate their proteostasis status to distal tissues. Here, we examine whether proteostasis of the germ line influences somatic tissues. To this end, we induce aggregation of germline-specific PGL-1 protein in germline stem cells of Caenorhabditis elegans Besides altering the intracellular mitochondrial network of germline cells, PGL-1 aggregation also reduces the mitochondrial content of somatic tissues through long-range Wnt signaling pathway. This process induces the unfolded protein response of the mitochondria in the soma, promoting somatic mitochondrial fragmentation and aggregation of proteins linked with neurodegenerative diseases such as Huntington's and amyotrophic lateral sclerosis. Thus, the proteostasis status of germline stem cells coordinates mitochondrial networks and protein aggregation through the organism.
    DOI:  https://doi.org/10.1126/sciadv.abg3012
  2. Mol Metab. 2021 Jun 18. pii: S2212-8778(21)00121-6. [Epub ahead of print] 101276
    HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue.
    Robert Hauffe, Michaela Rath, Mareike Schell, Katrin Ritter, Kai Kappert, Stefanie Deubel, Christiane Ott, Markus Jähnert, Wenke Jonas, Annette Schürmann, André Kleinridders.
      OBJECTIVE: Insulin regulates mitochondrial function, thereby propagating efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance.METHODS: Control and heterozygous whole-body HSP60 knock-out (Hsp60+/-) mice were fed a high-fat diet (HFD, 60% of calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was executed, ex vivo experiments performed and a lentiviral knockdown of Hsp60 in 3T3-L1 cells conducted to gain detailed insights into the effect of reduced Hsp60 levels on adipocyte homeostasis.
    RESULTS: Male Hsp60+/- mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/- mice in a glucose tolerance test. Yet, Hsp60+/- mice exhibited an altered adipose tissue metabolism with an elevated insulin-independent elevated glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy and local insulin resistance.
    CONCLUSION: We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology albeit exhibiting local insulin resistance.
    Keywords:  glucose homeostasis; insulin receptor; mitochondria; obesity; stress response
    DOI:  https://doi.org/10.1016/j.molmet.2021.101276
  3. Mol Cell. 2021 Jun 16. pii: S1097-2765(21)00451-2. [Epub ahead of print]
    Arginine monomethylation by PRMT7 controls MAVS-mediated antiviral innate immunity.
    Junji Zhu, Xiong Li, Xiaolian Cai, Huangyuan Zha, Ziwen Zhou, Xueyi Sun, Fangjing Rong, Jinghua Tang, Chunchun Zhu, Xing Liu, Sijia Fan, Jing Wang, Qian Liao, Gang Ouyang, Wuhan Xiao.
      Accurate control of innate immune responses is required to eliminate invading pathogens and simultaneously avoid autoinflammation and autoimmune diseases. Here, we demonstrate that arginine monomethylation precisely regulates the mitochondrial antiviral-signaling protein (MAVS)-mediated antiviral response. Protein arginine methyltransferase 7 (PRMT7) forms aggregates to catalyze MAVS monomethylation at arginine residue 52 (R52), attenuating its binding to TRIM31 and RIG-I, which leads to the suppression of MAVS aggregation and subsequent activation. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32 (R32), and SMURF1 is recruited to PRMT7 by MAVS to induce proteasomal degradation of PRMT7, resulting in the relief of PRMT7 suppression of MAVS activation. Therefore, we not only reveal that arginine monomethylation by PRMT7 negatively regulates MAVS-mediated antiviral signaling in vitro and in vivo but also uncover a mechanism by which PRMT7 is tightly controlled to ensure the timely activation of antiviral defense.
    Keywords:  MAVS; PRMT7; RIG-I; SMUFR1; TRIM31; arginine monomethylation; automethylation; innate immunity; virus infection
    DOI:  https://doi.org/10.1016/j.molcel.2021.06.004
  4. Dev Cell. 2021 Jun 24. pii: S1534-5807(21)00481-0. [Epub ahead of print]
    Mitochondrial-derived vesicles compensate for loss of LC3-mediated mitophagy.
    Christina G Towers, Darya K Wodetzki, Jacqueline Thorburn, Katharine R Smith, M Cecilia Caino, Andrew Thorburn.
      Mitochondria are critical metabolic and signaling hubs, and dysregulated mitochondrial homeostasis is implicated in many diseases. Degradation of damaged mitochondria by selective GABARAP/LC3-dependent macro-autophagy (mitophagy) is critical for maintaining mitochondrial homeostasis. To identify alternate forms of mitochondrial quality control that functionally compensate if mitophagy is inactive, we selected for autophagy-dependent cancer cells that survived loss of LC3-dependent autophagosome formation caused by inactivation of ATG7 or RB1CC1/FIP200. We discovered rare surviving autophagy-deficient clones that adapted to maintain mitochondrial homeostasis after gene inactivation and identified two enhanced mechanisms affecting mitochondria including mitochondrial dynamics and mitochondrial-derived vesicles (MDVs). To further understand these mechanisms, we quantified MDVs via flow cytometry and confirmed an SNX9-mediated mechanism necessary for flux of MDVs to lysosomes. We show that the autophagy-dependent cells acquire unique dependencies on these processes, indicating that these alternate forms of mitochondrial homeostasis compensate for loss of autophagy to maintain mitochondrial health.
    Keywords:  ATG7; FIP200; SNX9; autophagy; cancer; late endosomes; mitochondria; mitochondrial dynamics; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.1016/j.devcel.2021.06.003
  5. EMBO J. 2021 Jun 21. e100715
    Loss of neuronal Miro1 disrupts mitophagy and induces hyperactivation of the integrated stress response.
    Guillermo López-Doménech, Jack H Howden, Christian Covill-Cooke, Corinne Morfill, Jigna V Patel, Roland Bürli, Damian Crowther, Nicol Birsa, Nicholas J Brandon, Josef T Kittler.
      Clearance of mitochondria following damage is critical for neuronal homeostasis. Here, we investigate the role of Miro proteins in mitochondrial turnover by the PINK1/Parkin mitochondrial quality control system in vitro and in vivo. We find that upon mitochondrial damage, Miro is promiscuously ubiquitinated on multiple lysine residues. Genetic deletion of Miro or block of Miro1 ubiquitination and subsequent degradation lead to delayed translocation of the E3 ubiquitin ligase Parkin onto damaged mitochondria and reduced mitochondrial clearance in both fibroblasts and cultured neurons. Disrupted mitophagy in vivo, upon post-natal knockout of Miro1 in hippocampus and cortex, leads to a dramatic increase in mitofusin levels, the appearance of enlarged and hyperfused mitochondria and hyperactivation of the integrated stress response (ISR). Altogether, our results provide new insights into the central role of Miro1 in the regulation of mitochondrial homeostasis and further implicate Miro1 dysfunction in the pathogenesis of human neurodegenerative disease.
    Keywords:  Parkinson’s disease; Rhot1; Rhot2; eIF2α; megamitochondria
    DOI:  https://doi.org/10.15252/embj.2018100715
  6. J Biol Chem. 2021 Jun 19. pii: S0021-9258(21)00704-3. [Epub ahead of print] 100904
    Mitochondrial metabolism regulates macrophage biology.
    Yafang Wang, Na Li, Xin Zhang, Tiffany Horng.
      Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.
    Keywords:  macrophage activation; macrophage biology; mitochondrial dysfunction; mitochondrial metabolism; oxidative stress
    DOI:  https://doi.org/10.1016/j.jbc.2021.100904
  7. Biol Rev Camb Philos Soc. 2021 Jun 21.
    The mitochondrial permeability transition pore: an evolving concept critical for cell life and death.
    Giampaolo Morciano, Natalia Naumova, Piotr Koprowski, Sara Valente, Vilma A Sardão, Yaiza Potes, Alessandro Rimessi, Mariusz R Wieckowski, Paulo J Oliveira.
      In this review, we summarize current knowledge of perhaps one of the most intriguing phenomena in cell biology: the mitochondrial permeability transition pore (mPTP). This phenomenon, which was initially observed as a sudden loss of inner mitochondrial membrane impermeability caused by excessive calcium, has been studied for almost 50 years, and still no definitive answer has been provided regarding its mechanisms. From its initial consideration as an in vitro artifact to the current notion that the mPTP is a phenomenon with physiological and pathological implications, a long road has been travelled. We here summarize the role of mitochondria in cytosolic calcium control and the evolving concepts regarding the mitochondrial permeability transition (mPT) and the mPTP. We show how the evolving mPTP models and mechanisms, which involve many proposed mitochondrial protein components, have arisen from methodological advances and more complex biological models. We describe how scientific progress and methodological advances have allowed milestone discoveries on mPTP regulation and composition and its recognition as a valid target for drug development and a critical component of mitochondrial biology.
    Keywords:  calcium; cell death; mitochondria; mitochondrial permeability transition pore
    DOI:  https://doi.org/10.1111/brv.12764
  8. Proc Natl Acad Sci U S A. 2021 Jun 29. pii: e2100383118. [Epub ahead of print]118(26):
    Cellular nucleic acid-binding protein is essential for type I interferon-mediated immunity to RNA virus infection.
    Yongzhi Chen, Xuqiu Lei, Zhaozhao Jiang, Katherine A Fitzgerald.
      Type I interferons (IFNs) are innate immune cytokines required to establish cellular host defense. Precise control of IFN gene expression is crucial to maintaining immune homeostasis. Here, we demonstrated that cellular nucleic acid-binding protein (CNBP) was required for the production of type I IFNs in response to RNA virus infection. CNBP deficiency markedly impaired IFN production in macrophages and dendritic cells that were infected with a panel of RNA viruses or stimulated with synthetic double-stranded RNA. Furthermore, CNBP-deficient mice were more susceptible to influenza virus infection than were wild-type mice. Mechanistically, CNBP was phosphorylated and translocated to the nucleus, where it directly binds to the promoter of IFNb in response to RNA virus infection. Furthermore, CNBP controlled the recruitment of IFN regulatory factor (IRF) 3 and IRF7 to IFN promoters for the maximal induction of IFNb gene expression. These studies reveal a previously unrecognized role for CNBP as a transcriptional regulator of type I IFN genes engaged downstream of RNA virus-mediated innate immune signaling, which provides an additional layer of control for IRF3- and IRF7-dependent type I IFN gene expression and the antiviral innate immune response.
    Keywords:  CNBP; RNA virus; antiviral; transcriptional regulator; type I interferon
    DOI:  https://doi.org/10.1073/pnas.2100383118
  9. Cell Death Dis. 2021 Jun 19. 12(7): 632
    Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway.
    Zhengying Yu, Haipeng Wang, Wanyi Tang, Shaoyang Wang, Xiaoying Tian, Yujie Zhu, Hao He.
      Dysregulation of the PINK1/Parkin-mediated mitophagy is essential to Parkinson's disease. Although important progress has been made in previous researches, the biochemical reagents that induce global and significant mitochondrial damage may still hinder deeper insights into the mechanisms of mitophagy. The origin of PINK1/Parkin pathway activation in mitophagy remains elusive. In this study, we develop an optical method, ultra-precise laser stimulation (UPLaS) that delivers a precise and noninvasive stimulation onto a submicron region in a single mitochondrial tubular structure. UPLaS excites localized mitochondrial Ca2+ (mitoCa2+) oscillations with tiny perturbation to mitochondrial membrane potential (MMP) or mitochondrial reactive oxygen species. The UPLaS-induced mitoCa2+ oscillations can directly induce PINK1 accumulation and Parkin recruitment on mitochondria. The Parkin recruitment by UPLaS requires PINK1. Our results provide a precise and noninvasive technology for research on mitophagy, which stimulates target mitochondria with little damage, and reveal mitoCa2+ oscillation directly initiates the PINK1-Parkin pathway for mitophagy without MMP depolarization.
    DOI:  https://doi.org/10.1038/s41419-021-03913-3
  10. Cell Chem Biol. 2021 Jun 08. pii: S2451-9456(21)00260-9. [Epub ahead of print]
    Light-inducible deformation of mitochondria in live cells.
    Yutong Song, Peiyuan Huang, Xiaoying Liu, Zhihao Zhao, Yijin Wang, Bianxiao Cui, Liting Duan.
      Mitochondria, the powerhouse of the cell, are dynamic organelles that undergo constant morphological changes. Increasing evidence indicates that mitochondria morphologies and functions can be modulated by mechanical cues. However, the mechano-sensing and -responding properties of mitochondria and the relation between mitochondrial morphologies and functions are unclear due to the lack of methods to precisely exert mechano-stimulation on and deform mitochondria inside live cells. Here, we present an optogenetic approach that uses light to induce deformation of mitochondria by recruiting molecular motors to the outer mitochondrial membrane via light-activated protein-protein hetero-dimerization. Mechanical forces generated by motor proteins distort the outer membrane, during which the inner mitochondrial membrane can also be deformed. Moreover, this optical method can achieve subcellular spatial precision and be combined with different optical dimerizers and molecular motors. This method presents a mitochondria-specific mechano-stimulator for studying mitochondria mechanobiology and the interplay between mitochondria shapes and functions.
    Keywords:  cryptochrome 2; light-gated hetero-dimerization; mitochondria; mitochondrial morphology; molecular motor; optical dimerizer; optogenetics; organelle mechanobiology
    DOI:  https://doi.org/10.1016/j.chembiol.2021.05.015
  11. Endocrinol Metab (Seoul). 2021 Jun 22.
    Expression of LONP1 Is High in Visceral Adipose Tissue in Obesity, and Is Associated with Glucose and Lipid Metabolism.
    Ju Hee Lee, Saet-Byel Jung, Seong Eun Lee, Ji Eun Kim, Jung Tae Kim, Yea Eun Kang, Seul Gi Kang, Hyon-Seung Yi, Young Bok Ko, Ki Hwan Lee, Bon Jeong Ku, Minho Shong, Hyun Jin Kim.
      Background: The nature and role of the mitochondrial stress response in adipose tissue in relation to obesity are not yet known. To determine whether the mitochondrial unfolded protein response (UPRmt) in adipose tissue is associated with obesity in humans and rodents.Methods: Visceral adipose tissue (VAT) was obtained from 48 normoglycemic women who underwent surgery. Expression levels of mRNA and proteins were measured for mitochondrial chaperones, intrinsic proteases, and components of electron-transport chains. Furthermore, we systematically analyzed metabolic phenotypes with a large panel of isogenic BXD inbred mouse strains and Genotype-Tissue Expression (GTEx) data.
    Results: In VAT, expression of mitochondrial chaperones and intrinsic proteases localized in inner and outer mitochondrial membranes was not associated with body mass index (BMI), except for the Lon protease homolog, mitochondrial, and the corresponding gene LONP1, which showed high-level expression in the VAT of overweight or obese individuals. Expression of LONP1 in VAT positively correlated with BMI. Analysis of the GTEx database revealed that elevation of LONP1 expression is associated with enhancement of genes involved in glucose and lipid metabolism in VAT. Mice with higher Lonp1 expression in adipose tissue had better systemic glucose metabolism than mice with lower Lonp1 expression.
    Conclusion: Expression of mitochondrial LONP1, which is involved in the mitochondrial quality control stress response, was elevated in the VAT of obese individuals. In a bioinformatics analysis, high LONP1 expression in VAT was associated with enhanced glucose and lipid metabolism.
    Keywords:  Intra-abdominal fat; Metabolic syndrome; Obesity
    DOI:  https://doi.org/10.3803/EnM.2021.1023
  12. Cell Rep. 2021 Jun 22. pii: S2211-1247(21)00554-4. [Epub ahead of print]35(12): 109205
    DHX15 is required to control RNA virus-induced intestinal inflammation.
    Junji Xing, Xiaojing Zhou, Mingli Fang, Evan Zhang, Laurie J Minze, Zhiqiang Zhang.
      RNA helicases play critical roles in various biological processes, including serving as viral RNA sensors in innate immunity. Here, we find that RNA helicase DEAH-box helicase 15 (DHX15) is essential for type I interferon (IFN-I, IFN-β), type III IFN (IFN-λ3), and inflammasome-derived cytokine IL-18 production by intestinal epithelial cells (IECs) in response to poly I:C and RNA viruses with preference of enteric RNA viruses, but not DNA virus. Importantly, we generate IEC-specific Dhx15-knockout mice and demonstrate that DHX15 is required for controlling intestinal inflammation induced by enteric RNA virus rotavirus in suckling mice and reovirus in adult mice in vivo, which owes to impaired IFN-β, IFN-λ3, and IL-18 production in IECs from Dhx15-deficient mice. Mechanistically, DHX15 interacts with NLRP6 to trigger NLRP6 inflammasome assembly and activation for inducing IL-18 secretion in IECs. Collectively, our report reveals critical roles for DHX15 in sensing enteric RNA viruses in IECs and controlling intestinal inflammation.
    DOI:  https://doi.org/10.1016/j.celrep.2021.109205
  13. Nat Commun. 2021 06 22. 12(1): 3838
    Gut microbiota mediate the FGF21 adaptive stress response to chronic dietary protein-restriction in mice.
    Anthony Martin, Gertrude Ecklu-Mensah, Connie W Y Ha, Gustaf Hendrick, Donald K Layman, Jack Gilbert, Suzanne Devkota.
      Chronic dietary protein-restriction can create essential amino acid deficiencies and induce metabolic adaptation through the hepatic FGF21 pathway which serves to maintain host fitness during prolonged states of nutritional imbalance. Similarly, the gut microbiome undergoes metabolic adaptations when dietary nutrients are added or withdrawn. Here we confirm previous reports that dietary protein-restriction triggers the hepatic FGF21 adaptive metabolic pathway and further demonstrate that this response is mediated by the gut microbiome and can be tuned through dietary supplementation of fibers that alter the gut microbiome. In the absence of a gut microbiome, we discover that FGF21 is de-sensitized to the effect of protein-restriction. These data suggest that host-intrinsic adaptive pathways to chronic dietary protein-restriction, such as the hepatic FGF21 pathway, may in-fact be responding first to adaptive metabolic changes in the gut microbiome.
    DOI:  https://doi.org/10.1038/s41467-021-24074-z
  14. J Exp Med. 2021 Aug 02. pii: e20202446. [Epub ahead of print]218(8):
    GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.
    Peng Xu, Jerry C Chang, Xiaopu Zhou, Wei Wang, Michael Bamkole, Eitan Wong, Karima Bettayeb, Lu-Lin Jiang, Timothy Huang, Wenjie Luo, Huaxi Xu, Angus C Nairn, Marc Flajolet, Nancy Y Ip, Yue-Ming Li, Paul Greengard.
      Biochemical, pathogenic, and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer's disease (AD) and Down's syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the Fe65-APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization and that lowering GSAP expression reduces pathological effects associated with AD.
    DOI:  https://doi.org/10.1084/jem.20202446
  15. Proc Natl Acad Sci U S A. 2021 Jun 22. pii: e2023647118. [Epub ahead of print]118(25):
    TAK1 inhibition elicits mitochondrial ROS to block intracellular bacterial colonization.
    Wilfred López-Pérez, Kazuhito Sai, Yosuke Sakamachi, Cameron Parsons, Sophia Kathariou, Jun Ninomiya-Tsuji.
      Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is an intracellular signaling intermediate of inflammatory responses. However, a series of mouse Tak1 gene deletion analyses have revealed that ablation of TAK1 does not prevent but rather elicits inflammation, which is accompanied by elevation of reactive oxygen species (ROS). This has been considered a consequence of impaired TAK1-dependent maintenance of tissue integrity. Contrary to this view, here we propose that TAK1 inhibition-induced ROS are an active cellular process that targets intracellular bacteria. Intracellular bacterial effector proteins such as Yersinia's outer membrane protein YopJ are known to inhibit TAK1 to circumvent the inflammatory host responses. We found that such TAK1 inhibition induces mitochondrial-derived ROS, which effectively destroys intracellular bacteria. Two cell death-signaling molecules, caspase 8 and RIPK3, cooperatively participate in TAK1 inhibition-induced ROS and blockade of intracellular bacterial growth. Our results reveal a previously unrecognized host defense mechanism, which is initiated by host recognition of pathogen-induced impairment in a host protein, TAK1, but not directly of pathogens.
    Keywords:  ROS; TAK1; intracellular bacteria; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2023647118
  16. Cell Rep. 2021 Jun 22. pii: S2211-1247(21)00639-2. [Epub ahead of print]35(12): 109272
    Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation.
    Yong Shen, Kejun Tang, Dongdong Chen, Mengying Hong, Fangfang Sun, SaiSai Wang, Yuehai Ke, Tingting Wu, Ren Sun, Jing Qian, Yushen Du.
      The type I interferon (IFN) pathway is a key component of innate immune response upon invasion of foreign pathogens. It is also under precise control to prevent excessive upregulation and undesired inflammation cascade. In the present study, we report that Riok3, an atypical kinase, negatively regulates retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) sensing-induced type I IFN signaling. Riok3 deficiency selectively inhibits RNA viral replication in vitro, resulting from an upregulated type I IFN pathway. Mice with myeloid-specific Riok3 knockout also show a more robust induction of type I IFN upon RNA virus infection and are more resistant to RNA virus-induced pathogenesis. Mechanistically, Riok3 recruits and interacts with the E3 ubiquitin ligase TRIM40, leading to the degradation of RIG-I and melanoma differentiation-associated gene-5 (MDA5) via K48- and K27-linked ubiquitination. Collectively, our data reveal the mechanism that Riok3 employs to be a negative regulator of antiviral innate immunity.
    DOI:  https://doi.org/10.1016/j.celrep.2021.109272
  17. Autophagy. 2021 Jun 21. 1-17
    BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy.
    Guangtong Deng, Chaoran Li, Lang Chen, Changsheng Xing, Chuntang Fu, Chen Qian, Xin Liu, Helen Y Wang, Motao Zhu, Rong-Fu Wang.
      Macroautophagy/autophagy-related proteins regulate infectious and inflammatory diseases in autophagy-dependent or -independent manner. However, the role of a newly identified mammalian-specific autophagy protein-BECN2 (beclin 2) in innate immune regulation is largely unknown. Here we showed that loss of BECN2 enhanced the activities of NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes upon ligand stimulations. Mechanistically, BECN2 interacted with inflammasome sensors and mediated their degradation through a ULK1- and ATG9A-dependent, but BECN1-WIPI2-ATG16L1-LC3-independent, non-canonical autophagic pathway. BECN2 recruited inflammasome sensors on ATG9A+ vesicles to form a complex (BECN2-ATG9A-sensors) upon ULK1 activation. Three soluble NSF attachment protein receptor (SNARE) proteins (SEC22A, STX5, and STX6) were further shown to mediate the BECN2-ATG9A-dependent inflammasome sensor degradation. Loss of BECN2 promoted alum-induced peritonitis, which could be rescued by the ablation of CASP1 in Becn2-deficient mice. Hence, BECN2 negatively regulated inflammasome activation to control inflammation, serving as a potential therapeutic target for the treatment of infectious and inflammatory diseases.Abbreviations: AIM2: absent in melanoma 2; ATG: autophagy related; BECN1: beclin 1; BMDC: bone marrow-derived dendritic cells; BMDM: bone marrow-derived macrophages; CASP1: caspase 1; CQ: chloroquine; gMDSC: granulocytic myeloid-derived suppressor cells; IL: interleukin; LPS: lipopolysaccharide; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; mMDSC: monocytic myeloid-derived suppressor cells; NLRC4: NLR family CARD domain containing 4; NLRP1: NLR family pyrin domain containing 1; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PYCARD/ASC: apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; SNAREs: soluble NSF attachment protein receptors; STX5: syntaxin 5; STX6: syntaxin 6; ULK1: unc-51 like autophagy activating kinase 1; WIPI: WD repeat domain, phosphoinositide interacting.
    Keywords:  ATG9A; Alum-induced peritonitis; BECN2; STX5-STX6-SEC22A-mediated membrane fusion; inflammasome; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1934270
  18. Cell Chem Biol. 2021 Jun 12. pii: S2451-9456(21)00261-0. [Epub ahead of print]
    Intracellular H2S production is an autophagy-dependent adaptive response to DNA damage.
    Xiaofeng Jiang, Michael R MacArthur, J Humberto Treviño-Villarreal, Peter Kip, C Keith Ozaki, Sarah J Mitchell, James R Mitchell.
      Hydrogen sulfide (H2S) is a gasotransmitter with broad physiological activities, including protecting cells against stress, but little is known about the regulation of cellular H2S homeostasis. We have performed a high-content small-molecule screen and identified genotoxic agents, including cancer chemotherapy drugs, as activators of intracellular H2S levels. DNA damage-induced H2S in vitro and in vivo. Mechanistically, DNA damage elevated autophagy and upregulated H2S-generating enzyme CGL; chemical or genetic disruption of autophagy or CGL impaired H2S induction. Importantly, exogenous H2S partially rescued autophagy-deficient cells from genotoxic stress. Furthermore, stressors that are not primarily genotoxic (growth factor depletion and mitochondrial uncoupler FCCP) increased intracellular H2S in an autophagy-dependent manner. Our findings highlight the role of autophagy in H2S production and suggest that H2S generation may be a common adaptive response to DNA damage and other stressors.
    Keywords:  CGL enzyme; DNA damage response; P3 probe; SF7-AM probe; autophagy; cancer chemotherapy; high-throughput screening; hydrogen sulfide; stress response; sulfide metabolism
    DOI:  https://doi.org/10.1016/j.chembiol.2021.05.016
  19. J Biol Chem. 2021 Jun 16. pii: S0021-9258(21)00684-0. [Epub ahead of print] 100884
    mTORC1 Activation is Not Sufficient to Suppress Hepatic PPARα Signaling or Ketogenesis.
    Ebru S Selen, Michael J Wolfgang.
      The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of cellular metabolism that can integrate growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the Tuberous Sclerosis Complex (TSC), a negative regulator of mTORC1, in order to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate PPARα signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L-/-) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Further, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using Cpt2L-/- mice. We generated liver-specific Cpt2L-/-; Tsc1L-/- double knockout mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L-/- mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis following fasting.
    Keywords:  Ketogenesis; carnitine palmitoyltransferase 2 (Cpt2); fatty acid oxidation; mTOR; metabolism; peroxisome proliferator-activated receptor alpha (PPARα); β-hydroxybutyrate (βHB)
    DOI:  https://doi.org/10.1016/j.jbc.2021.100884
  20. Mitochondrion. 2021 Jun 19. pii: S1567-7249(21)00083-0. [Epub ahead of print]
    Blood Mitochondrial DNA Copy Number: What Are We Counting?
    Martin Picard.
      There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the mitochondrial DNA (mtDNA), and it has been proposed that the number of mtDNA copies per cell (mtDNA copy number; mtDNAcn) reflects mitochondrial health. The common availability of stored DNA material or existing DNA sequencing data, especially from blood and other easy-to-collect samples, has made its quantification a popular approach in clinical and epidemiological studies. However, the interpretation of mtDNAcn is not univocal, and either a reduction or elevation in mtDNAcn can indicate dysfunction. The major determinants of blood-derived mtDNAcn are the heterogeneous cell type composition of leukocytes and platelet abundance, which can change with time of day, aging, and with disease. Hematopoiesis as a likely driver of blood mtDNAcn. Here we discuss the rationale and available methods to quantify mtDNAcn, the influence of blood cell type variations, and consider important gaps in knowledge that need to be resolved to maximize the scientific output around the investigation of blood mtDNAcn in humans.
    Keywords:  White blood cells; biomarker; count; leukocytes; mitochondrial function; mitochondrial genome; mitochondrion
    DOI:  https://doi.org/10.1016/j.mito.2021.06.010
  21. EMBO J. 2021 Jun 21. e107240
    N-glycan processing selects ERAD-resistant misfolded proteins for ER-to-lysosome-associated degradation.
    Ilaria Fregno, Elisa Fasana, Tatiana Soldà, Carmela Galli, Maurizio Molinari.
      Efficient degradation of by-products of protein biogenesis maintains cellular fitness. Strikingly, the major biosynthetic compartment in eukaryotic cells, the endoplasmic reticulum (ER), lacks degradative machineries. Misfolded proteins in the ER are translocated to the cytosol for proteasomal degradation via ER-associated degradation (ERAD). Alternatively, they are segregated in ER subdomains that are shed from the biosynthetic compartment and are delivered to endolysosomes under control of ER-phagy receptors for ER-to-lysosome-associated degradation (ERLAD). Demannosylation of N-linked oligosaccharides targets terminally misfolded proteins for ERAD. How misfolded proteins are eventually marked for ERLAD is not known. Here, we show for ATZ and mutant Pro-collagen that cycles of de-/re-glucosylation of selected N-glycans and persistent association with Calnexin (CNX) are required and sufficient to mark ERAD-resistant misfolded proteins for FAM134B-driven lysosomal delivery. In summary, we show that mannose and glucose processing of N-glycans are triggering events that target misfolded proteins in the ER to proteasomal (ERAD) and lysosomal (ERLAD) clearance, respectively, regulating protein quality control in eukaryotic cells.
    Keywords:  ER-phagy; ERAD; ERLAD; N-glycan processing; Protein quality control
    DOI:  https://doi.org/10.15252/embj.2020107240
  22. Hum Mol Genet. 2021 Jun 24. pii: ddab168. [Epub ahead of print]
    Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.
    Xiaoshan Zhou, Flora Mikaeloff, Sophie Curbo, Qian Zhao, Raoul V Kuiper, Ákos Végvári, Ujjwal Neogi, Anna Karlsson.
      Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok-/-) mice despite low (<5%) mtDNA content in liver tissue. However, the molecular mechanisms enabling the extended survival remain unknown. Using transcriptomics, proteomics and metabolomics followed by in vitro assays, we aimed to identify the molecular pathways involved in the extended survival of the Dguok-/- mice. At the early stage, the serine synthesis and folate cycle were activated but declined later. Increased activity of the mitochondrial citric acid cycle (TCA cycle) and the urea cycle and degradation of branched chain amino acids were hallmarks of the extended lifespan in DGUOK deficiency. Furthermore, the increased synthesis of TCA cycle intermediates was supported by coordination of two pyruvate kinase genes, PKLR and PKM, indicating a central coordinating role of pyruvate kinases to support the long-term survival in mitochondrial dysfunction.
    DOI:  https://doi.org/10.1093/hmg/ddab168
  23. Anal Methods. 2021 Jun 25.
    Real-time imaging of viscosity in the mitochondrial matrix by a red-emissive molecular rotor.
    Lin Yuan, Dong Wang, Shan Shan, Juan Chen, Wei Huang, Guangmei Han, Xiaohe Tian, Ruilong Zhang, Zhongping Zhang, Zhengjie Liu.
      Mitochondrial matrix contains numerous metabolism-related proteins/enzymes and nucleic acids, which play key roles in the process of energy generation and signal transduction. The fluctuations in mitochondrial biomacromolecular levels lead to the changes in the mitochondrial matrix viscosity; therefore, real-time measuring the mitochondrial matrix viscosity is of great significance for the in-depth understanding of the mitochondrial physiology and pathobiology. However, investigations are limited due to the lack of a mitochondrial matrix-specific molecular rotor. Herein, we report a design of a molecular rotor that is specifically enriched in the mitochondrial matrix. The red fluorescence of the rotor switches on when the viscosity increases, enabling the real-time monitoring of the viscosity change therein. Interestingly, the rotor showed non-fluorescence behaviour in the liposome (mimicking membrane structure), avoiding fluorescence interference from the mitochondrial bilayer membrane. Super-resolution imaging reveals that the viscosity is uneven in an individual mitochondrion.
    DOI:  https://doi.org/10.1039/d1ay00366f
  24. mSystems. 2021 Jun 22. e0039721
    The DNA Sensor IFIX Drives Proteome Alterations To Mobilize Nuclear and Cytoplasmic Antiviral Responses, with Its Acetylation Acting as a Localization Toggle.
    Timothy R Howard, Marni S Crow, Todd M Greco, Krystal K Lum, Tuo Li, Ileana M Cristea.
      DNA sensors are critical components of innate immunity that enable cells to recognize infection by pathogens with DNA genomes. The interferon-inducible protein X (IFIX), a member of the PYHIN protein family, is a DNA sensor capable of promoting immune signaling after binding to double-stranded DNA (dsDNA) within either the nucleus or cytoplasm. Here, we investigate the impact of IFIX on the cellular proteome upon introduction of foreign DNA to the nucleus or the cytoplasm as well as regulatory hubs that control IFIX subcellular localization. Using quantitative mass spectrometry, we define the effect of CRISPR-mediated IFIX knockout on nuclear and cytoplasmic proteomes in fibroblasts. Proteomes are probed in response to either nuclear viral DNA, during herpes simplex virus 1 (HSV-1) infection, or cytoplasmic viral DNA, following transfection with dsDNA derived from vaccinia virus (VACV 70-mer). We show that IFIX broadly impacts nuclear and cytoplasmic proteomes, inducing alterations in the abundances of immune signaling, DNA damage response, and vesicle-mediated transport proteins. To characterize IFIX properties that regulate its localization during DNA sensing, we perform deletion and mutagenesis assays. We find that IFIX contains a multipartite nuclear localization signal (NLS) and highlight the main contributing motif for its nuclear localization. Using immunoaffinity purification, we identify IFIX acetylation and phosphorylation sites. Mutations to acetyl or charge mimics demonstrate that K138 acetylation, positioned within the NLS, affects nuclear localization. Altogether, our study establishes a mechanism regulating IFIX subcellular localization and contextualizes this localization with the involvement of IFIX in host cell responses to pathogenic DNA. IMPORTANCE Mammalian cells must be able to detect and respond to invading pathogens to prevent the spread of infection. DNA sensors, such as IFIX, are proteins that bind to pathogen-derived double-stranded DNA and induce antiviral cytokine expression. Here, we characterize the host proteome changes that require IFIX during both viral infection and DNA transfection. We show IFIX mobilizes numerous pathways and proteome alterations within the nucleus and the cytoplasm, pointing to a multifunctional protein with roles in immune signaling, DNA damage response, and transcriptional regulation. We next interrogate the IFIX domains required for nuclear localization, discovering its regulation via a multipartite nuclear localization motif. The acetylation of this motif promotes IFIX cytoplasmic localization, in agreement with its detection of pathogenic DNA in both the nucleus and the cytoplasm. This study established NLS acetylation as a conserved mechanism for regulating the localization of nuclear DNA sensors from the PYHIN family of proteins.
    Keywords:  DNA sensing; HSV-1; IFIX; innate immunity; lysine acetylation; mass spectrometry; posttranslational modification; proteomics
    DOI:  https://doi.org/10.1128/mSystems.00397-21
  25. Sci Rep. 2021 Jun 25. 11(1): 13316
    Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome.
    Katharina Cosker, Anna Mallach, Janhavi Limaye, Thomas M Piers, James Staddon, Stephen J Neame, John Hardy, Jennifer M Pocock.
      The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer's disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD.
    DOI:  https://doi.org/10.1038/s41598-021-91207-1
  26. Cell Death Dis. 2021 Jun 23. 12(7): 643
    Western diet leads to aging-related tumorigenesis via activation of the inflammatory, UPR, and EMT pathways.
    Ricardo Imbroisi Filho, Alan C Ochioni, Amanda M Esteves, João G B Leandro, Thainá M Demaria, Mauro Sola-Penna, Patricia Zancan.
      Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial-mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.
    DOI:  https://doi.org/10.1038/s41419-021-03929-9
  27. mSphere. 2021 Jun 23. e0047921
    Rhinovirus Reduces the Severity of Subsequent Respiratory Viral Infections by Interferon-Dependent and -Independent Mechanisms.
    James T Van Leuven, Andres J Gonzalez, Emmanuel C Ijezie, Alexander Q Wixom, John L Clary, Maricris N Naranjo, Benjamin J Ridenhour, Craig R Miller, Tanya A Miura.
      Coinfection by heterologous viruses in the respiratory tract is common and can alter disease severity compared to infection by individual virus strains. We previously found that inoculation of mice with rhinovirus (RV) 2 days before inoculation with a lethal dose of influenza A virus [A/Puerto Rico/8/34 (H1N1) (PR8)] provides complete protection against mortality. Here, we extended that finding to a second lethal respiratory virus, pneumonia virus of mice (PVM), and analyzed potential mechanisms of RV-induced protection. RV completely prevented mortality and weight loss associated with PVM infection. Major changes in host gene expression upon PVM infection were delayed compared to PR8. RV induced earlier recruitment of inflammatory cells, which were reduced at later times in RV-inoculated mice. Findings common to both virus pairs included the upregulated expression of mucin-associated genes and dampening of inflammation-related genes in mice that were inoculated with RV before lethal virus infection. However, type I interferon (IFN) signaling was required for RV-mediated protection against PR8 but not PVM. IFN signaling had minor effects on PR8 replication and contributed to controlling neutrophilic inflammation and hemorrhagic lung pathology in RV/PR8-infected mice. These findings, combined with differences in virus replication levels and disease severity, suggest that the suppression of inflammation in RV/PVM-infected mice may be due to early, IFN-independent suppression of viral replication, while that in RV/PR8-infected mice may be due to IFN-dependent modulation of immune responses. Thus, a mild upper respiratory viral infection can reduce the severity of a subsequent severe viral infection in the lungs through virus-dependent mechanisms. IMPORTANCE Respiratory viruses from diverse families cocirculate in human populations and are frequently detected within the same host. Although clinical studies suggest that infection by multiple different respiratory viruses may alter disease severity, animal models in which we can control the doses, timing, and strains of coinfecting viruses are critical to understanding how coinfection affects disease severity. Here, we compared gene expression and immune cell recruitment between two pairs of viruses (RV/PR8 and RV/PVM) inoculated sequentially in mice, both of which result in reduced severity compared to lethal infection by PR8 or PVM alone. Reduced disease severity was associated with suppression of inflammatory responses in the lungs. However, differences in disease kinetics and host and viral gene expression suggest that protection by coinfection with RV may be due to distinct molecular mechanisms. Indeed, we found that antiviral cytokine signaling was required for RV-mediated protection against lethal infection by PR8 but not PVM.
    Keywords:  influenza; interferons; mouse model; pneumovirus; respiratory viruses; rhinovirus
    DOI:  https://doi.org/10.1128/mSphere.00479-21
  28. Front Mol Biosci. 2021 ;8 671363
    Sex-Related Overactivation of NLRP3 Inflammasome Increases Lethality of the Male COVID-19 Patients.
    Hongliang Zhang, Yujie Tang, Jinhui Tao.
      The COVID-19 pandemic, caused by SARS-CoV-2 infection, remains a dramatic threat to human life and economic well-being worldwide. Significant heterogeneity in the severity of disease was observed for patients infected with SARS-CoV-2 ranging from asymptomatic to severe cases. Moreover, male patients had a higher probability of suffering from high mortality and severe symptoms linked to cytokine storm and excessive inflammation. The NLRP3 inflammasome is presumably critical to this process. Sex differences may directly affect the activation of NLRP3 inflammasome, impacting the severity of observed COVID-19 symptoms. To elucidate the potential mechanisms underlying sex based differences in NLRP3 activation during SARS-CoV-2 infection, this review summarizes the reported mechanisms and identifies potential therapeutic targets.
    Keywords:  COVID-19; NLRP3 inflammasome; P2X7R; SARS-CoV-2; cytokine storm; sex
    DOI:  https://doi.org/10.3389/fmolb.2021.671363
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