Pub Date : 2024-01-02DOI: 10.1126/scisignal.adn0865
Arun K. Shukla
{"title":"The expanding footprint of basic biology research in India","authors":"Arun K. Shukla","doi":"10.1126/scisignal.adn0865","DOIUrl":"10.1126/scisignal.adn0865","url":null,"abstract":"","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adn0865","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139081064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-02DOI: 10.1126/scisignal.adg4422
Alexandre Poirier, João Vitor Silva Ormonde, Isabelle Aubry, Belma Melda Abidin, Chu-Han Feng, Zuzet Martinez-Cordova, Ana Maria Hincapie, Chenyue Wu, Luis Alberto Pérez-Quintero, Chia-Lin Wang, Anne Claude Gingras, Joaquín Madrenas, Michel L. Tremblay
Thousand-and-one–amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naïve CD4+ T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on Taok3 gene dosage and on Taok3 kinase activity. TCR desensitization in Taok3−/− T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes.
{"title":"The induction of SHP-1 degradation by TAOK3 ensures the responsiveness of T cells to TCR stimulation","authors":"Alexandre Poirier, João Vitor Silva Ormonde, Isabelle Aubry, Belma Melda Abidin, Chu-Han Feng, Zuzet Martinez-Cordova, Ana Maria Hincapie, Chenyue Wu, Luis Alberto Pérez-Quintero, Chia-Lin Wang, Anne Claude Gingras, Joaquín Madrenas, Michel L. Tremblay","doi":"10.1126/scisignal.adg4422","DOIUrl":"10.1126/scisignal.adg4422","url":null,"abstract":"<div >Thousand-and-one–amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naïve CD4<sup>+</sup> T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on <i>Taok3</i> gene dosage and on Taok3 kinase activity. TCR desensitization in <i>Taok3<sup>−/−</sup></i> T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139081065","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 : 2023-12-19DOI: 10.1126/scisignal.adg5289
Antje Schaefer, Richard G. Hodge, Haisheng Zhang, G. Aaron Hobbs, Julien Dilly, Minh V. Huynh, Craig M. Goodwin, Feifei Zhang, J. Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U. Rashid, Emanuel F. Petricoin, Adrienne D. Cox, William C. Hahn, Andrew J. Aguirre, Adam J. Bass, Channing J. Der
Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr 42 -to-Cys (Y42C) and Leu 57 -to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA Y42C exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA L57V promotes DGC growth. In mouse gastric organoids with deletion of Cdh1 , which encodes the cell adhesion protein E-cadherin, the expression of RHOA L57V , but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA L57V also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA L57V retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr 42 and Leu 57 in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA L57V additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA Y42C . Our results reveal that RHOA L57V and RHOA Y42C drive the development of DGC through distinct biochemical and signaling mechanisms.
{"title":"RHOA L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling","authors":"Antje Schaefer, Richard G. Hodge, Haisheng Zhang, G. Aaron Hobbs, Julien Dilly, Minh V. Huynh, Craig M. Goodwin, Feifei Zhang, J. Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U. Rashid, Emanuel F. Petricoin, Adrienne D. Cox, William C. Hahn, Andrew J. Aguirre, Adam J. Bass, Channing J. Der","doi":"10.1126/scisignal.adg5289","DOIUrl":"https://doi.org/10.1126/scisignal.adg5289","url":null,"abstract":"Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr <jats:sup>42</jats:sup> -to-Cys (Y42C) and Leu <jats:sup>57</jats:sup> -to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA <jats:sup>Y42C</jats:sup> exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA <jats:sup>L57V</jats:sup> promotes DGC growth. In mouse gastric organoids with deletion of <jats:italic>Cdh1</jats:italic> , which encodes the cell adhesion protein E-cadherin, the expression of RHOA <jats:sup>L57V</jats:sup> , but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA <jats:sup>L57V</jats:sup> also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA <jats:sup>L57V</jats:sup> retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr <jats:sup>42</jats:sup> and Leu <jats:sup>57</jats:sup> in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA <jats:sup>L57V</jats:sup> additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA <jats:sup>Y42C</jats:sup> . Our results reveal that RHOA <jats:sup>L57V</jats:sup> and RHOA <jats:sup>Y42C</jats:sup> drive the development of DGC through distinct biochemical and signaling mechanisms.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138818839","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 : 2023-12-19DOI: 10.1126/scisignal.ade0326
Luca Mazzarella, Fabio Santoro, Roberto Ravasio, Valeria Fumagalli, Paul E. Massa, Simona Rodighiero, Elena Gavilán, Mauro Romanenghi, Bruno A. Duso, Emanuele Bonetti, Lara Manganaro, Rani Pallavi, Deborah Trastulli, Isabella Pallavicini, Claudia Gentile, Silvia Monzani, Tommaso Leonardi, Sebastiano Pasqualato, Gabriele Buttinelli, Angela Di Martino, Giorgio Fedele, Ilaria Schiavoni, Paola Stefanelli, Giuseppe Meroni, Raffaele de Francesco, Christian Steinkuhler, Gianluca Fossati, Matteo Iannacone, Saverio Minucci, Pier Giuseppe Pelicci
Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB–dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.
{"title":"Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses","authors":"Luca Mazzarella, Fabio Santoro, Roberto Ravasio, Valeria Fumagalli, Paul E. Massa, Simona Rodighiero, Elena Gavilán, Mauro Romanenghi, Bruno A. Duso, Emanuele Bonetti, Lara Manganaro, Rani Pallavi, Deborah Trastulli, Isabella Pallavicini, Claudia Gentile, Silvia Monzani, Tommaso Leonardi, Sebastiano Pasqualato, Gabriele Buttinelli, Angela Di Martino, Giorgio Fedele, Ilaria Schiavoni, Paola Stefanelli, Giuseppe Meroni, Raffaele de Francesco, Christian Steinkuhler, Gianluca Fossati, Matteo Iannacone, Saverio Minucci, Pier Giuseppe Pelicci","doi":"10.1126/scisignal.ade0326","DOIUrl":"https://doi.org/10.1126/scisignal.ade0326","url":null,"abstract":"Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB–dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138819049","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 : 2023-12-19DOI: 10.1126/scisignal.adh3449
Yuanyuan Li, Richa B. Shah, Samanta Sarti, Alicia L. Belcher, Brian J. Lee, Andrej Gorbatenko, Francesca Nemati, Honglin Yu, Zoe Stanley, Mahbuba Rahman, Zhengping Shao, Jose M. Silva, Shan Zha, Samuel Sidi
Interleukin-1 receptor (IL-1R)–associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 and IRAK1 together inhibited DNA damage–induced cell death independently of TLR or IL-1R signaling. In human cancer cells, IRAK4 was activated downstream of ATR kinase in response to double-strand breaks (DSBs) induced by ionizing radiation (IR). Activated IRAK4 then formed a complex with and activated IRAK1. The formation of this complex required the E3 ubiquitin ligase Pellino1, acting structurally but not catalytically, and the activation of IRAK1 occurred independently of extracellular signaling, intracellular TLRs, and the TLR/IL-1R signaling adaptor MyD88. Activated IRAK1 translocated to the nucleus in a Pellino2-dependent manner. In the nucleus, IRAK1 bound to the PIDD1 subunit of the proapoptotic PIDDosome and interfered with platform assembly, thus supporting cell survival. This noncanonical IRAK signaling pathway was also activated in response to other DSB-inducing agents. The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments.
{"title":"A noncanonical IRAK4-IRAK1 pathway counters DNA damage–induced apoptosis independently of TLR/IL-1R signaling","authors":"Yuanyuan Li, Richa B. Shah, Samanta Sarti, Alicia L. Belcher, Brian J. Lee, Andrej Gorbatenko, Francesca Nemati, Honglin Yu, Zoe Stanley, Mahbuba Rahman, Zhengping Shao, Jose M. Silva, Shan Zha, Samuel Sidi","doi":"10.1126/scisignal.adh3449","DOIUrl":"https://doi.org/10.1126/scisignal.adh3449","url":null,"abstract":"Interleukin-1 receptor (IL-1R)–associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 and IRAK1 together inhibited DNA damage–induced cell death independently of TLR or IL-1R signaling. In human cancer cells, IRAK4 was activated downstream of ATR kinase in response to double-strand breaks (DSBs) induced by ionizing radiation (IR). Activated IRAK4 then formed a complex with and activated IRAK1. The formation of this complex required the E3 ubiquitin ligase Pellino1, acting structurally but not catalytically, and the activation of IRAK1 occurred independently of extracellular signaling, intracellular TLRs, and the TLR/IL-1R signaling adaptor MyD88. Activated IRAK1 translocated to the nucleus in a Pellino2-dependent manner. In the nucleus, IRAK1 bound to the PIDD1 subunit of the proapoptotic PIDDosome and interfered with platform assembly, thus supporting cell survival. This noncanonical IRAK signaling pathway was also activated in response to other DSB-inducing agents. The loss of IRAK4, of IRAK4 kinase activity, of either Pellino protein, or of the nuclear localization sequence in IRAK1 sensitized p53-mutant zebrafish to radiation. Thus, the findings may lead to strategies for overcoming tumor resistance to conventional cancer treatments.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138818840","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 : 2023-12-19DOI: 10.1126/scisignal.adk9171
Dorothy Benton, Jonathan Chernoff
Oncogenic small guanosine triphosphatases (GTPases) are often characterized by a limited set of activating mutations that affect their intrinsic biochemical function, but RHOA—which is frequently mutated in gastric cancer—appears not to have read the instruction manual. Having previously characterized the Y42C RHOA mutation in gastric cancer, in this issue of Science Signaling , Schaefer et al. take on the slightly less common L57V mutation and find that individual RHOA mutations can have different and unpredictable signaling outcomes.
{"title":"RHOA drivers take alternate routes in gastric cancer","authors":"Dorothy Benton, Jonathan Chernoff","doi":"10.1126/scisignal.adk9171","DOIUrl":"https://doi.org/10.1126/scisignal.adk9171","url":null,"abstract":"Oncogenic small guanosine triphosphatases (GTPases) are often characterized by a limited set of activating mutations that affect their intrinsic biochemical function, but RHOA—which is frequently mutated in gastric cancer—appears not to have read the instruction manual. Having previously characterized the Y42C RHOA mutation in gastric cancer, in this issue of <jats:italic>Science Signaling</jats:italic> , Schaefer <jats:italic>et al.</jats:italic> take on the slightly less common L57V mutation and find that individual RHOA mutations can have different and unpredictable signaling outcomes.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138818852","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 : 2023-12-12DOI: 10.1126/scisignal.abq1173
Zbigniew Korwek, Maciej Czerkies, Joanna Jaruszewicz-Błońska, Wiktor Prus, Ilona Kosiuk, Marek Kochańczyk, Tomasz Lipniacki
Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which, through activation of the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because of depletion of the interferon-β (IFN-β) receptor, IFNAR. Activation of RNase L and PKR, products of two ISGs, not only hindered the replenishment of IFNAR but also suppressed negative regulators of IRF3 and NF-κB, consequently promoting IFNB transcription. We incorporated these findings into a mathematical model of innate immunity. By coupling signaling through the IRF3–NF-κB and STAT1/2 pathways with the activities of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from being STAT1/2 induced to being IRF3 and NF-κB induced, which converts IFN-β–responding cells to IFN-β–secreting cells.
{"title":"Nonself RNA rewires IFN-β signaling: A mathematical model of the innate immune response","authors":"Zbigniew Korwek, Maciej Czerkies, Joanna Jaruszewicz-Błońska, Wiktor Prus, Ilona Kosiuk, Marek Kochańczyk, Tomasz Lipniacki","doi":"10.1126/scisignal.abq1173","DOIUrl":"10.1126/scisignal.abq1173","url":null,"abstract":"<div >Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which, through activation of the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because of depletion of the interferon-β (IFN-β) receptor, IFNAR. Activation of RNase L and PKR, products of two ISGs, not only hindered the replenishment of IFNAR but also suppressed negative regulators of IRF3 and NF-κB, consequently promoting <i>IFNB</i> transcription. We incorporated these findings into a mathematical model of innate immunity. By coupling signaling through the IRF3–NF-κB and STAT1/2 pathways with the activities of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from being STAT1/2 induced to being IRF3 and NF-κB induced, which converts IFN-β–responding cells to IFN-β–secreting cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138580703","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}
{"title":"A caspase finds a target","authors":"Amy E. Baek","doi":"10.1126/scisignal.adn3720","DOIUrl":"10.1126/scisignal.adn3720","url":null,"abstract":"<div >The noncanonical caspase caspase-4 processes the pro form of IL-18 in response to LPS.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138812460","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 : 2023-12-12DOI: 10.1126/scisignal.adi9018
Kyle M. LaPak, Soma Saeidi, Ilah Bok, Nathan T. Wamsley, Isaac B. Plutzer, Dhaval P. Bhatt, Jingqin Luo, Ghazaleh Ashrafi, M. Ben Major
The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members NRF1, NRF3, and the NRF2 heterodimer MAFG. A functional screen of co-complexed proteins revealed previously uncharacterized regulators of NRF2 transcriptional activity. We found that ZNF746 (also known as PARIS), a zinc finger transcription factor implicated in Parkinson’s disease, physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 overexpression increased oxidative stress and apoptosis in a neuronal cell model of Parkinson’s disease, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests a link between ZNF746 overexpression in Parkinson’s disease and inhibition of NRF2-driven neuroprotection.
{"title":"Proximity proteomic analysis of the NRF family reveals the Parkinson’s disease protein ZNF746/PARIS as a co-complexed repressor of NRF2","authors":"Kyle M. LaPak, Soma Saeidi, Ilah Bok, Nathan T. Wamsley, Isaac B. Plutzer, Dhaval P. Bhatt, Jingqin Luo, Ghazaleh Ashrafi, M. Ben Major","doi":"10.1126/scisignal.adi9018","DOIUrl":"10.1126/scisignal.adi9018","url":null,"abstract":"<div >The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members NRF1, NRF3, and the NRF2 heterodimer MAFG. A functional screen of co-complexed proteins revealed previously uncharacterized regulators of NRF2 transcriptional activity. We found that ZNF746 (also known as PARIS), a zinc finger transcription factor implicated in Parkinson’s disease, physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 overexpression increased oxidative stress and apoptosis in a neuronal cell model of Parkinson’s disease, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests a link between ZNF746 overexpression in Parkinson’s disease and inhibition of NRF2-driven neuroprotection.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138580653","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 : 2023-12-05DOI: 10.1126/scisignal.adn2344
Leslie K. Ferrarelli
Physical exercise stimulates brain cells to secrete a β-amyloid–degrading enzyme.
体育锻炼能刺激脑细胞分泌一种β-淀粉样蛋白降解酶。
{"title":"Get moving to clear β-amyloid","authors":"Leslie K. Ferrarelli","doi":"10.1126/scisignal.adn2344","DOIUrl":"10.1126/scisignal.adn2344","url":null,"abstract":"<div >Physical exercise stimulates brain cells to secrete a β-amyloid–degrading enzyme.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138488885","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}
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