Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with mitochondrial antiviral signaling proteins (MAVSs) to activate IRF3 and nuclear factor κB (NF-κB) signaling, initiating innate immune responses. Thus, RLR activation plays a vital role in the removal of invasive RNA viruses while maintaining immune homeostasis. However, inadequate or excessive activation of immunity can cause harm and can even lead to lethal consequences. In this study, we identify an E3 ligase, ankyrin repeat and IBR domain containing 1 (ANKIB1), which suppresses RLR signaling via MAVS. ANKIB1 binds to MAVS to enhance K48-linked polyubiquitination with K311R, causing proteasomal degradation of MAVS. Deficiency of ANKIB1 significantly increases the RLR-mediated production of type I interferon (IFN) along with pro-inflammatory factors. Consequently, ANKIB1 deficiency remarkably increases antiviral immunity and decreases viral replication in vivo. Therefore, we reveal that ANKIB1 restricts RLR-induced innate immune activation, indicating its potential role as a therapeutic target for viral infections.
{"title":"E3 ubiquitin ligase ANKIB1 attenuates antiviral immune responses by promoting K48-linked polyubiquitination of MAVS.","authors":"Wei Liu, Cui Yuan, Buwen Fu, Jiufeng Xie, Wenqing Li, Guozhi Zhang, Zhenling Ma, Pengtao Jiao","doi":"10.1016/j.celrep.2024.114687","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114687","url":null,"abstract":"<p><p>Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with mitochondrial antiviral signaling proteins (MAVSs) to activate IRF3 and nuclear factor κB (NF-κB) signaling, initiating innate immune responses. Thus, RLR activation plays a vital role in the removal of invasive RNA viruses while maintaining immune homeostasis. However, inadequate or excessive activation of immunity can cause harm and can even lead to lethal consequences. In this study, we identify an E3 ligase, ankyrin repeat and IBR domain containing 1 (ANKIB1), which suppresses RLR signaling via MAVS. ANKIB1 binds to MAVS to enhance K48-linked polyubiquitination with K311R, causing proteasomal degradation of MAVS. Deficiency of ANKIB1 significantly increases the RLR-mediated production of type I interferon (IFN) along with pro-inflammatory factors. Consequently, ANKIB1 deficiency remarkably increases antiviral immunity and decreases viral replication in vivo. Therefore, we reveal that ANKIB1 restricts RLR-induced innate immune activation, indicating its potential role as a therapeutic target for viral infections.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1016/j.celrep.2024.114699
Frida Torell, Michael Dimitriou
Proprioception plays a crucial role in motor coordination and self-perception. Muscle spindles are the principal receptors for proprioception. They are believed to encode muscle stretch and signal limb position and velocity. Here, we applied percutaneous pressure to a small area of extensor muscles at the forearm while recording spindle afferent responses, skeletal muscle activity, and hand kinematics. Three levels of sustained pressure were applied on the spindle-bearing muscle when the hand was relaxed and immobile ("isometric" condition) and when the participant's hand moved rhythmically at the wrist. As hypothesized to occur due to compression of the spindle capsule, we show that muscle pressure is an "adequate" stimulus for human spindles in isometric conditions and that pressure enhances spindle responses during stretch. Interestingly, release of sustained pressure in isometric conditions lowered spindle firing below baseline rates. Our findings urge a re-evaluation of muscle proprioception in sensorimotor function and various neuromuscular pathologies.
{"title":"Local muscle pressure stimulates the principal receptors for proprioception.","authors":"Frida Torell, Michael Dimitriou","doi":"10.1016/j.celrep.2024.114699","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114699","url":null,"abstract":"<p><p>Proprioception plays a crucial role in motor coordination and self-perception. Muscle spindles are the principal receptors for proprioception. They are believed to encode muscle stretch and signal limb position and velocity. Here, we applied percutaneous pressure to a small area of extensor muscles at the forearm while recording spindle afferent responses, skeletal muscle activity, and hand kinematics. Three levels of sustained pressure were applied on the spindle-bearing muscle when the hand was relaxed and immobile (\"isometric\" condition) and when the participant's hand moved rhythmically at the wrist. As hypothesized to occur due to compression of the spindle capsule, we show that muscle pressure is an \"adequate\" stimulus for human spindles in isometric conditions and that pressure enhances spindle responses during stretch. Interestingly, release of sustained pressure in isometric conditions lowered spindle firing below baseline rates. Our findings urge a re-evaluation of muscle proprioception in sensorimotor function and various neuromuscular pathologies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1016/j.celrep.2024.114704
Matthew I J Raybould, Alexander Greenshields-Watson, Parth Agarwal, Broncio Aguilar-Sanjuan, Tobias H Olsen, Oliver M Turnbull, Nele P Quast, Charlotte M Deane
T cell activation is governed through T cell receptors (TCRs), heterodimers of two sequence-variable chains (often an α and β chain) that synergistically recognize antigen fragments presented on cell surfaces. Despite this, there only exist repositories dedicated to collecting single-chain, not paired-chain, TCR sequence data. We addressed this gap by creating the Observed TCR Space (OTS) database, a source of consistently processed and annotated, full-length, paired-chain TCR sequences. Currently, OTS contains 5.35 million redundant (1.63 million non-redundant), predominantly human sequences from across 50 studies and at least 75 individuals. Using OTS, we identify pairing biases, public TCRs, and distinct chain coherence patterns relative to antibodies. We also release a paired-chain TCR language model, providing paired embedding representations and a method for residue in-filling conditional on the partner chain. OTS will be updated as a central community resource and is freely downloadable and available as a web application.
{"title":"The Observed T Cell Receptor Space database enables paired-chain repertoire mining, coherence analysis, and language modeling.","authors":"Matthew I J Raybould, Alexander Greenshields-Watson, Parth Agarwal, Broncio Aguilar-Sanjuan, Tobias H Olsen, Oliver M Turnbull, Nele P Quast, Charlotte M Deane","doi":"10.1016/j.celrep.2024.114704","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114704","url":null,"abstract":"<p><p>T cell activation is governed through T cell receptors (TCRs), heterodimers of two sequence-variable chains (often an α and β chain) that synergistically recognize antigen fragments presented on cell surfaces. Despite this, there only exist repositories dedicated to collecting single-chain, not paired-chain, TCR sequence data. We addressed this gap by creating the Observed TCR Space (OTS) database, a source of consistently processed and annotated, full-length, paired-chain TCR sequences. Currently, OTS contains 5.35 million redundant (1.63 million non-redundant), predominantly human sequences from across 50 studies and at least 75 individuals. Using OTS, we identify pairing biases, public TCRs, and distinct chain coherence patterns relative to antibodies. We also release a paired-chain TCR language model, providing paired embedding representations and a method for residue in-filling conditional on the partner chain. OTS will be updated as a central community resource and is freely downloadable and available as a web application.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1016/j.celrep.2024.114670
Jiabo Li, Hao Wang, Pengjiao Ma, Tao Li, Jiakui Ren, Jingyu Zhang, Mi Zhou, Yuhang He, Teng Yang, Wenhui He, Man-Tian Mi, Yang-Wuyue Liu, Shuang-Shuang Dai
Neutrophils from skull bone marrow (Nskull) are activated under some brain stresses, but their effects on traumatic brain injury (TBI) are lacking. Here, we find Nskull infiltrates brain tissue quickly and persistently after TBI, which is distinguished by highly and specifically expressed osteocalcin (OCN) from blood-derived neutrophils (Nblood). Reprogramming of glucose metabolism by reducing glycolysis-related enzyme glyceraldehyde 3-phosphate dehydrogenase expression is involved in the antiapoptotic and proliferative abilities of OCN-expressing Nskull. The transcription factor Fos-like 1 governs the specific gene profile of Nskull including C-C motif chemokine receptor-like 2 (CCRL2), arginase 1 (Arg1), and brain-derived neurotrophic factor (BDNF) in addition to OCN. Selective knockout of CCRL2 in Nskull demonstrates that CCRL2 mediates its recruitment, whereas high Arg1 expression is consistent with its immunosuppressive effects on Nblood, and the secretion of BDNF facilitating dendritic growth contributes to its neuroprotection. Thus, our findings provide insight into the roles of Nskull in TBI.
{"title":"Osteocalcin-expressing neutrophils from skull bone marrow exert immunosuppressive and neuroprotective effects after TBI.","authors":"Jiabo Li, Hao Wang, Pengjiao Ma, Tao Li, Jiakui Ren, Jingyu Zhang, Mi Zhou, Yuhang He, Teng Yang, Wenhui He, Man-Tian Mi, Yang-Wuyue Liu, Shuang-Shuang Dai","doi":"10.1016/j.celrep.2024.114670","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114670","url":null,"abstract":"<p><p>Neutrophils from skull bone marrow (N<sub>skull</sub>) are activated under some brain stresses, but their effects on traumatic brain injury (TBI) are lacking. Here, we find N<sub>skull</sub> infiltrates brain tissue quickly and persistently after TBI, which is distinguished by highly and specifically expressed osteocalcin (OCN) from blood-derived neutrophils (N<sub>blood</sub>). Reprogramming of glucose metabolism by reducing glycolysis-related enzyme glyceraldehyde 3-phosphate dehydrogenase expression is involved in the antiapoptotic and proliferative abilities of OCN-expressing N<sub>skull</sub>. The transcription factor Fos-like 1 governs the specific gene profile of N<sub>skull</sub> including C-C motif chemokine receptor-like 2 (CCRL2), arginase 1 (Arg1), and brain-derived neurotrophic factor (BDNF) in addition to OCN. Selective knockout of CCRL2 in N<sub>skull</sub> demonstrates that CCRL2 mediates its recruitment, whereas high Arg1 expression is consistent with its immunosuppressive effects on N<sub>blood</sub>, and the secretion of BDNF facilitating dendritic growth contributes to its neuroprotection. Thus, our findings provide insight into the roles of N<sub>skull</sub> in TBI.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1016/j.celrep.2024.114684
Wonyeong Jung, Arturo Abdelnour, Paulina Kaplonek, Rolando Herrero, Jessica Shih-Lu Lee, Domenic R Barbati, Taras M Chicz, Kate S Levine, Romain Clement Fantin, Viviana Loria, Carolina Porras, Douglas A Lauffenburger, Mitchell H Gail, Amada Aparicio, Allan Hildesheim, Galit Alter, Ryan P McNamara
Immunity acquired by vaccination following infection, termed hybrid immunity, has been shown to confer enhanced protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by enhancing the breadth and potency of immune responses. Here, we assess Fc-mediated humoral profiles in hybrid immunity and their association with age and vaccine type. Participants are divided into three groups: infection only, vaccination only, and vaccination following infection (i.e., hybrid immunity). Using systems serology, we profile humoral immune responses against spikes and subdomains of SARS-CoV-2 variants. We find that hybrid immunity is characterized by superior Fc receptor binding and natural killer (NK) cell-, neutrophil-, and complement-activating antibodies, which is higher than what can be expected from the sum of the vaccination and infection. These differences between hybrid immunity and vaccine-induced immunity are more pronounced in aged adults, especially for immunoglobulin (Ig)G1, IgG2, and Fcγ receptor-binding antibodies. Our findings suggest that vaccination strategies that aim to mimic hybrid immunity should consider age as an important modifier.
感染后通过接种疫苗获得的免疫力被称为混合免疫力,已被证明可通过提高免疫反应的广度和效力来增强对严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)的保护。在此,我们对混合免疫中 Fc 介导的体液特征及其与年龄和疫苗类型的关系进行了评估。参与者分为三组:仅感染组、仅接种组和感染后接种组(即混合免疫组)。我们利用系统血清学分析了针对 SARS-CoV-2 变体的尖峰和亚域的体液免疫反应。我们发现,混合免疫的特点是超强的 Fc 受体结合力以及自然杀伤(NK)细胞、中性粒细胞和补体激活抗体,这高于疫苗接种和感染的总和。混合免疫和疫苗诱导免疫之间的这些差异在老年人中更为明显,尤其是免疫球蛋白(Ig)G1、IgG2 和 Fcγ 受体结合抗体。我们的研究结果表明,旨在模拟混合免疫的疫苗接种策略应将年龄作为一个重要的调节因素。
{"title":"SARS-CoV-2 infection prior to vaccination amplifies Fc-mediated humoral profiles in an age-dependent manner.","authors":"Wonyeong Jung, Arturo Abdelnour, Paulina Kaplonek, Rolando Herrero, Jessica Shih-Lu Lee, Domenic R Barbati, Taras M Chicz, Kate S Levine, Romain Clement Fantin, Viviana Loria, Carolina Porras, Douglas A Lauffenburger, Mitchell H Gail, Amada Aparicio, Allan Hildesheim, Galit Alter, Ryan P McNamara","doi":"10.1016/j.celrep.2024.114684","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114684","url":null,"abstract":"<p><p>Immunity acquired by vaccination following infection, termed hybrid immunity, has been shown to confer enhanced protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by enhancing the breadth and potency of immune responses. Here, we assess Fc-mediated humoral profiles in hybrid immunity and their association with age and vaccine type. Participants are divided into three groups: infection only, vaccination only, and vaccination following infection (i.e., hybrid immunity). Using systems serology, we profile humoral immune responses against spikes and subdomains of SARS-CoV-2 variants. We find that hybrid immunity is characterized by superior Fc receptor binding and natural killer (NK) cell-, neutrophil-, and complement-activating antibodies, which is higher than what can be expected from the sum of the vaccination and infection. These differences between hybrid immunity and vaccine-induced immunity are more pronounced in aged adults, especially for immunoglobulin (Ig)G1, IgG2, and Fcγ receptor-binding antibodies. Our findings suggest that vaccination strategies that aim to mimic hybrid immunity should consider age as an important modifier.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.celrep.2024.114703
Shiwei Chen, Wan Rong Sia, Leon J W Tang, Akshamal M Gamage, Wharton O Y Chan, Feng Zhu, Wanni Chia, Madeline S S Kwek, Pui San Kong, Beng Lee Lim, Randy Foo, Wei Lun Ng, Adrian H J Tan, Abigail Y T Loh, Dolyce H W Low, Gavin J D Smith, Lewis Z Hong, Lin-Fa Wang
Among their many unique biological features, bats are increasingly recognized as a key reservoir of many emerging viruses that cause massive morbidity and mortality in humans. Bats are capable of harboring many of these deadly viruses without any apparent signs of pathology, in a mechanism known as viral disease tolerance. However, the immunological mechanisms behind viral tolerance remain poorly understood. As a non-model organism species, there are very limited research resources and tools available to study bat immunology. In the cave nectar bat Eonycteris spelaea, we have a panel of monoclonal antibodies (mAbs) against major immune markers. An immunophenotyping survey of major immune compartments and barrier sites using these mAbs reveals differences in the immunological landscape of bats.
{"title":"Application of a bespoke monoclonal antibody panel to characterize immune cell populations in cave nectar bats.","authors":"Shiwei Chen, Wan Rong Sia, Leon J W Tang, Akshamal M Gamage, Wharton O Y Chan, Feng Zhu, Wanni Chia, Madeline S S Kwek, Pui San Kong, Beng Lee Lim, Randy Foo, Wei Lun Ng, Adrian H J Tan, Abigail Y T Loh, Dolyce H W Low, Gavin J D Smith, Lewis Z Hong, Lin-Fa Wang","doi":"10.1016/j.celrep.2024.114703","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114703","url":null,"abstract":"<p><p>Among their many unique biological features, bats are increasingly recognized as a key reservoir of many emerging viruses that cause massive morbidity and mortality in humans. Bats are capable of harboring many of these deadly viruses without any apparent signs of pathology, in a mechanism known as viral disease tolerance. However, the immunological mechanisms behind viral tolerance remain poorly understood. As a non-model organism species, there are very limited research resources and tools available to study bat immunology. In the cave nectar bat Eonycteris spelaea, we have a panel of monoclonal antibodies (mAbs) against major immune markers. An immunophenotyping survey of major immune compartments and barrier sites using these mAbs reveals differences in the immunological landscape of bats.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.celrep.2024.114692
Farshad Amiri, Ayuba A Akinpelu, William C Keith, Farnaz Hemmati, Ravi S Vaghasiya, Dylan Bowen, Razan S Waliagha, Chuanyu Wang, Pengyu Chen, Amit K Mitra, Yizeng Li, Panagiotis Mistriotis
Our understanding of how fluid forces influence cell migration in confining environments remains limited. By integrating microfluidics with live-cell imaging, we demonstrate that cells in tightly-but not moderately-confined spaces reverse direction and move upstream upon exposure to fluid forces. This fluid force-induced directional change occurs less frequently when cells display diminished mechanosensitivity, experience elevated hydraulic resistance, or sense a chemical gradient. Cell reversal requires actin polymerization to the new cell front, as shown mathematically and experimentally. Actin polymerization is necessary for the fluid force-induced activation of NHE1, which cooperates with calcium to induce upstream migration. Calcium levels increase downstream, mirroring the subcellular distribution of myosin IIA, whose activation enhances upstream migration. Reduced lamin A/C levels promote downstream migration of metastatic tumor cells by preventing cell polarity establishment and intracellular calcium rise. This mechanism could allow cancer cells to evade high-pressure environments, such as the primary tumor.
{"title":"Confinement controls the directional cell responses to fluid forces.","authors":"Farshad Amiri, Ayuba A Akinpelu, William C Keith, Farnaz Hemmati, Ravi S Vaghasiya, Dylan Bowen, Razan S Waliagha, Chuanyu Wang, Pengyu Chen, Amit K Mitra, Yizeng Li, Panagiotis Mistriotis","doi":"10.1016/j.celrep.2024.114692","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114692","url":null,"abstract":"<p><p>Our understanding of how fluid forces influence cell migration in confining environments remains limited. By integrating microfluidics with live-cell imaging, we demonstrate that cells in tightly-but not moderately-confined spaces reverse direction and move upstream upon exposure to fluid forces. This fluid force-induced directional change occurs less frequently when cells display diminished mechanosensitivity, experience elevated hydraulic resistance, or sense a chemical gradient. Cell reversal requires actin polymerization to the new cell front, as shown mathematically and experimentally. Actin polymerization is necessary for the fluid force-induced activation of NHE1, which cooperates with calcium to induce upstream migration. Calcium levels increase downstream, mirroring the subcellular distribution of myosin IIA, whose activation enhances upstream migration. Reduced lamin A/C levels promote downstream migration of metastatic tumor cells by preventing cell polarity establishment and intracellular calcium rise. This mechanism could allow cancer cells to evade high-pressure environments, such as the primary tumor.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1016/j.celrep.2024.114682
Hui-Ru Chen, Yidan Sun, Gerhard Mittler, Tobias Rumpf, Maria Shvedunova, Rudolf Grosschedl, Asifa Akhtar
Signaling-dependent changes in protein phosphorylation are critical to enable coordination of transcription and metabolism during macrophage activation. However, the role of acetylation in signal transduction during macrophage activation remains obscure. Here, we identify the redox signaling regulator peroxiredoxin 1 (PRDX1) as a substrate of the lysine acetyltransferase MOF. MOF acetylates PRDX1 at lysine 197, preventing hyperoxidation and thus maintaining its activity under stress. PRDX1 K197ac responds to inflammatory signals, decreasing rapidly in mouse macrophages stimulated with bacterial lipopolysaccharides (LPSs) but not with interleukin (IL)-4 or IL-10. The LPS-induced decrease of PRDX1 K197ac elevates cellular hydrogen peroxide accumulation and augments ERK1/2, but not p38 or AKT, phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Our work reveals a regulatory role for redox protein acetylation in signal transduction and coordinating metabolic and transcriptional programs during inflammatory macrophage activation.
{"title":"MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.","authors":"Hui-Ru Chen, Yidan Sun, Gerhard Mittler, Tobias Rumpf, Maria Shvedunova, Rudolf Grosschedl, Asifa Akhtar","doi":"10.1016/j.celrep.2024.114682","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114682","url":null,"abstract":"<p><p>Signaling-dependent changes in protein phosphorylation are critical to enable coordination of transcription and metabolism during macrophage activation. However, the role of acetylation in signal transduction during macrophage activation remains obscure. Here, we identify the redox signaling regulator peroxiredoxin 1 (PRDX1) as a substrate of the lysine acetyltransferase MOF. MOF acetylates PRDX1 at lysine 197, preventing hyperoxidation and thus maintaining its activity under stress. PRDX1 K197ac responds to inflammatory signals, decreasing rapidly in mouse macrophages stimulated with bacterial lipopolysaccharides (LPSs) but not with interleukin (IL)-4 or IL-10. The LPS-induced decrease of PRDX1 K197ac elevates cellular hydrogen peroxide accumulation and augments ERK1/2, but not p38 or AKT, phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Our work reveals a regulatory role for redox protein acetylation in signal transduction and coordinating metabolic and transcriptional programs during inflammatory macrophage activation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27Epub Date: 2024-07-29DOI: 10.1016/j.celrep.2024.114559
Mattie J Casey, Priya P Chan, Qing Li, Ju-Fen Zu, Cicely A Jette, Missia Kohler, Benjamin R Myers, Rodney A Stewart
Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ∼30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe a zebrafish model of SHH MB using CRISPR to create mutant ptch1, the primary genetic driver of human SHH MB. In these animals, tumors rapidly arise in the cerebellum and resemble human SHH MB by histology and comparative onco-genomics. Similar to human patients, MB tumors with loss of both ptch1 and tp53 have aggressive tumor histology and significantly worse survival outcomes. The simplicity and scalability of the ptch1-crispant MB model makes it highly amenable to CRISPR-based genome-editing screens to identify genes required for SHH MB tumor formation in vivo, and here we identify the gene encoding Grk3 kinase as one such target.
{"title":"A simple and scalable zebrafish model of Sonic hedgehog medulloblastoma.","authors":"Mattie J Casey, Priya P Chan, Qing Li, Ju-Fen Zu, Cicely A Jette, Missia Kohler, Benjamin R Myers, Rodney A Stewart","doi":"10.1016/j.celrep.2024.114559","DOIUrl":"10.1016/j.celrep.2024.114559","url":null,"abstract":"<p><p>Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ∼30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe a zebrafish model of SHH MB using CRISPR to create mutant ptch1, the primary genetic driver of human SHH MB. In these animals, tumors rapidly arise in the cerebellum and resemble human SHH MB by histology and comparative onco-genomics. Similar to human patients, MB tumors with loss of both ptch1 and tp53 have aggressive tumor histology and significantly worse survival outcomes. The simplicity and scalability of the ptch1-crispant MB model makes it highly amenable to CRISPR-based genome-editing screens to identify genes required for SHH MB tumor formation in vivo, and here we identify the gene encoding Grk3 kinase as one such target.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27Epub Date: 2024-08-06DOI: 10.1016/j.celrep.2024.114644
Kunpeng Qin, Shuai Jiang, Hang Xu, Zihao Yuan, Li Sun
{"title":"Pyroptotic gasdermin exists in Mollusca and is vital to eliminating bacterial infection.","authors":"Kunpeng Qin, Shuai Jiang, Hang Xu, Zihao Yuan, Li Sun","doi":"10.1016/j.celrep.2024.114644","DOIUrl":"10.1016/j.celrep.2024.114644","url":null,"abstract":"","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}