Han Fang, Mengling Shi, Cong Wang, Saiting Zhang, Na Kong, Mengyao Ji, Yan Wang, Yidan Zhou, Qiyun Zhu, Yu Zhang, Shishen Du, Shuai Xu, Caoqi Lei
Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. Pcsk9 −/− mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus–host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.
{"title":"PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and degradation of VISA/MAVS","authors":"Han Fang, Mengling Shi, Cong Wang, Saiting Zhang, Na Kong, Mengyao Ji, Yan Wang, Yidan Zhou, Qiyun Zhu, Yu Zhang, Shishen Du, Shuai Xu, Caoqi Lei","doi":"10.1073/pnas.2412206122","DOIUrl":"https://doi.org/10.1073/pnas.2412206122","url":null,"abstract":"Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. <jats:italic> Pcsk9 <jats:sup>−/−</jats:sup> </jats:italic> mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus–host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"361 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-30DOI: 10.1073/pnas.2500424122
{"title":"Correction for Li et al., Recurrent DNA nicks drive massive expansions of (GAA)<sub>n</sub> repeats.","authors":"","doi":"10.1073/pnas.2500424122","DOIUrl":"https://doi.org/10.1073/pnas.2500424122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2500424122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets.com/MALL), provide a framework for the metabolism-centered management of ALL.
{"title":"Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia.","authors":"Jun-Yu Wang, Tuan-Tuan Gui, Bo Jiao, Xuan Liu, Xiao-Lin Ma, Cheng Wang, Jing Qiao, Wei-Yang Liu, Li-Jun Peng, Jia-Yi Ren, Yong-Mei Zhu, Xiang-Qin Weng, Chao Wang, Qian-Qian Zhang, Gao-Xian Song, Yu-Ting Dai, Zhen-Yi Wang, Gang Lv, Chen-Xu Gao, Niu Qiao, Ming Zhang, Yun Tan, Yuan-Fang Liu, Sheng-Yue Wang, Jian Hou, Duo-Hui Jing, An-Kang Lyu, Jian-Qing Mi, Zhu Chen, Wen-Lian Chen, Tong Yin, Hai Fang, Jin Wang, Sai-Juan Chen","doi":"10.1073/pnas.2423169122","DOIUrl":"https://doi.org/10.1073/pnas.2423169122","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets.com/MALL), provide a framework for the metabolism-centered management of ALL.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2423169122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-02-12DOI: 10.1073/pnas.2410246122
Philippe Rufin, Patrick Meyfroidt, Felicia O Akinyemi, Lyndon Estes, Esther Shupel Ibrahim, Meha Jain, Hannah Kerner, Sá Nogueira Lisboa, David Lobell, Catherine Nakalembe, Claudio Persello, Michelle C A Picoli, Natasha Ribeiro, Almeida Alberto Sitoe, Katharina Waha, Sherrie Wang
{"title":"To enhance sustainable development goal research, open up commercial satellite image archives.","authors":"Philippe Rufin, Patrick Meyfroidt, Felicia O Akinyemi, Lyndon Estes, Esther Shupel Ibrahim, Meha Jain, Hannah Kerner, Sá Nogueira Lisboa, David Lobell, Catherine Nakalembe, Claudio Persello, Michelle C A Picoli, Natasha Ribeiro, Almeida Alberto Sitoe, Katharina Waha, Sherrie Wang","doi":"10.1073/pnas.2410246122","DOIUrl":"https://doi.org/10.1073/pnas.2410246122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2410246122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-30DOI: 10.1073/pnas.2427297122
{"title":"Correction for Hasson et al., Automated determination of transport and depositional environments in sand and sandstones.","authors":"","doi":"10.1073/pnas.2427297122","DOIUrl":"https://doi.org/10.1073/pnas.2427297122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2427297122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-01-30DOI: 10.1073/pnas.2500334122
{"title":"Correction for Joshy et al., Accelerated cell-type-specific regulatory evolution of the human brain.","authors":"","doi":"10.1073/pnas.2500334122","DOIUrl":"https://doi.org/10.1073/pnas.2500334122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2500334122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-02-06DOI: 10.1073/pnas.2426753122
{"title":"Correction for Sun et al., JFK, a Kelch domain-containing F-box protein, links the SCF complex to p53 regulation.","authors":"","doi":"10.1073/pnas.2426753122","DOIUrl":"https://doi.org/10.1073/pnas.2426753122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2426753122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-02-10DOI: 10.1073/pnas.2426773122
Aviram Rasouly, Evgeny Nudler
{"title":"In the shadow of antibiotics.","authors":"Aviram Rasouly, Evgeny Nudler","doi":"10.1073/pnas.2426773122","DOIUrl":"https://doi.org/10.1073/pnas.2426773122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2426773122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julia L. Bachman, Siân R. Kitcher, Lucas G. Vattino, Holly J. Beaulac, M. Grace Chaves, Israel Hernandez Rivera, Eleonora Katz, Carolina Wedemeyer, Catherine J. C. Weisz
Cochlear outer hair cells (OHCs) are electromotile and implicated in amplification of responses to sound that enhance sound sensitivity and frequency tuning. They send afferent information through glutamatergic synapses onto type II spiral ganglion neurons (SGNs). These synapses are weaker than those from cochlear inner hair cells onto type I SGN, suggesting that type II SGNs respond only to intense sound levels. OHCs also receive efferent innervation from medial olivocochlear (MOC) neurons. MOC neurons are cholinergic yet inhibit OHCs due to the functional coupling of alpha9/alpha10 nicotinic acetylcholine receptors (nAChRs) to calcium-activated SK potassium channels. The resulting hyperpolarization reduces OHC activity-evoked electromotility and is implicated in cochlear gain control, protection against acoustic trauma, and attention. MOC neurons also label for markers of GABA and GABA synthesis. GABA B autoreceptor (GABA B R) activation on MOC terminals has been demonstrated to reduce ACh release, confirming important negative feedback roles. However, the full complement of GABAergic activity in the cochlea is not currently understood, including mechanisms of GABA release from MOC axons, whether GABA diffuses from MOC axons to other postsynaptic cells, and the location and function of GABA A receptors (GABA A Rs). We used optical neurotransmitter detection, immunohistochemistry, and patch-clamp electrophysiology to demonstrate that in addition to presynaptic GABA B autoreceptor activation, MOC efferent terminals release GABA onto type II SGN afferent dendrites with postsynaptic activity mediated by GABA A Rs. This synapse may have roles including developmental regulation of cochlear innervation, fine-tuning of OHC activity, or providing feedback to the brain about MOC and OHC activity.
{"title":"GABAergic synapses between auditory efferent neurons and type II spiral ganglion afferent neurons in the mouse cochlea","authors":"Julia L. Bachman, Siân R. Kitcher, Lucas G. Vattino, Holly J. Beaulac, M. Grace Chaves, Israel Hernandez Rivera, Eleonora Katz, Carolina Wedemeyer, Catherine J. C. Weisz","doi":"10.1073/pnas.2409921122","DOIUrl":"https://doi.org/10.1073/pnas.2409921122","url":null,"abstract":"Cochlear outer hair cells (OHCs) are electromotile and implicated in amplification of responses to sound that enhance sound sensitivity and frequency tuning. They send afferent information through glutamatergic synapses onto type II spiral ganglion neurons (SGNs). These synapses are weaker than those from cochlear inner hair cells onto type I SGN, suggesting that type II SGNs respond only to intense sound levels. OHCs also receive efferent innervation from medial olivocochlear (MOC) neurons. MOC neurons are cholinergic yet inhibit OHCs due to the functional coupling of alpha9/alpha10 nicotinic acetylcholine receptors (nAChRs) to calcium-activated SK potassium channels. The resulting hyperpolarization reduces OHC activity-evoked electromotility and is implicated in cochlear gain control, protection against acoustic trauma, and attention. MOC neurons also label for markers of GABA and GABA synthesis. GABA <jats:sub>B</jats:sub> autoreceptor (GABA <jats:sub>B</jats:sub> R) activation on MOC terminals has been demonstrated to reduce ACh release, confirming important negative feedback roles. However, the full complement of GABAergic activity in the cochlea is not currently understood, including mechanisms of GABA release from MOC axons, whether GABA diffuses from MOC axons to other postsynaptic cells, and the location and function of GABA <jats:sub>A</jats:sub> receptors (GABA <jats:sub>A</jats:sub> Rs). We used optical neurotransmitter detection, immunohistochemistry, and patch-clamp electrophysiology to demonstrate that in addition to presynaptic GABA <jats:sub>B</jats:sub> autoreceptor activation, MOC efferent terminals release GABA onto type II SGN afferent dendrites with postsynaptic activity mediated by GABA <jats:sub>A</jats:sub> Rs. This synapse may have roles including developmental regulation of cochlear innervation, fine-tuning of OHC activity, or providing feedback to the brain about MOC and OHC activity.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"36 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-18Epub Date: 2025-02-11DOI: 10.1073/pnas.2501149122
{"title":"Retraction for Hiramatsu et al., DAT (deacylating autotransporter toxin) from <i>Bordetella parapertussis</i> demyristoylates Gα<sub>i</sub> GTPases and contributes to cough.","authors":"","doi":"10.1073/pnas.2501149122","DOIUrl":"https://doi.org/10.1073/pnas.2501149122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 7","pages":"e2501149122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}