Journal of Experimental Medicine最新文献_第3页

Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis. 淋巴流出通道对脑脊液稳态的不同影响。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-02-03 Epub Date: 2025-01-08 DOI: 10.1084/jem.20241752

Zachary Papadopoulos, Leon C D Smyth, Igor Smirnov, Daniel A Gibson, Jasmin Herz, Jonathan Kipnis

{"title":"Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis.","authors":"Zachary Papadopoulos, Leon C D Smyth, Igor Smirnov, Daniel A Gibson, Jasmin Herz, Jonathan Kipnis","doi":"10.1084/jem.20241752","DOIUrl":"10.1084/jem.20241752","url":null,"abstract":"Dysfunctional lymphatic drainage from the central nervous system (CNS) has been linked to neuroinflammatory and neurodegenerative disorders, but our understanding of the lymphatic contribution to CNS fluid autoregulation remains limited. Here, we studied forces that drive the outflow of the cerebrospinal fluid (CSF) into the deep and superficial cervical lymph nodes (dcLN and scLN) and tested how the blockade of lymphatic networks affects CNS fluid homeostasis. Outflow to the dcLN occurred spontaneously in the absence of lymphatic pumping and was coupled to intracranial pressure (ICP), whereas scLN drainage was driven by pumping. Impaired dcLN drainage led to elevated CSF outflow resistance and delayed CSF-to-blood efflux despite the recruitment of the nasal-to-scLN pathway. Fluid regulation was better compensated after scLN obstruction. The dcLN pathway exhibited steady, consistent drainage across conditions, while the nasal-to-scLN pathway was dynamically activated to mitigate perturbances. These findings highlight the complex physiology of CSF homeostasis and lay the groundwork for future studies aimed at assessing and modulating CNS lymphatic function.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 2","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11708779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The phospholipid kinase PIKFYVE is essential for Th17 differentiation. 磷脂激酶PIKFYVE对Th17的分化至关重要。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-02-03 Epub Date: 2024-12-31 DOI: 10.1084/jem.20240625

Douglas S Prado, Richard T Cattley, Andreza B Sonego, Parth Sutariya, Shuxian Wu, Mijoon Lee, William C Boggess, Mark J Shlomchik, William F Hawse

{"title":"The phospholipid kinase PIKFYVE is essential for Th17 differentiation.","authors":"Douglas S Prado, Richard T Cattley, Andreza B Sonego, Parth Sutariya, Shuxian Wu, Mijoon Lee, William C Boggess, Mark J Shlomchik, William F Hawse","doi":"10.1084/jem.20240625","DOIUrl":"10.1084/jem.20240625","url":null,"abstract":"T helper 17 (Th17) cells are effector cells that mediate inflammatory responses to bacterial and fungal pathogens. While the cytokine signaling inputs required to generate Th17s are established, less is known about intracellular pathways that drive Th17 differentiation. Our previously published phosphoproteomic screen identifies that PIKFYVE, a lipid kinase that generates the phosphatidylinositol PtdIns(3,5)P2, is activated during Th17 differentiation. Herein, we discovered that PIKFYVE regulates kinase and transcription factor networks to promote Th17 differentiation. As a specific example, PtdIns(3,5)P2 directly stimulates mTORC1 kinase activity to promote cell division and differentiation pathways. Furthermore, PIKFYVE promotes STAT3 phosphorylation, which is required for Th17 differentiation. Chemical inhibition or CD4-specific deletion of PIKFYVE reduces Th17 differentiation and autoimmune pathology in the experimental autoimmune encephalomyelitis murine model of multiple sclerosis. Our findings identify molecular mechanisms by which PIKFYVE promotes Th17 differentiation and suggest that PIKFYVE is a potential therapeutic target in Th17-driven autoimmune diseases.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 2","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of α-galactosylceramide as an endogenous mammalian antigen for iNKT cells. α-半乳糖神经酰胺作为哺乳动物iNKT细胞内源性抗原的鉴定。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-02-03 Epub Date: 2024-12-20 DOI: 10.1084/jem.20240728

Yuki Hosono, Noriyuki Tomiyasu, Hayato Kasai, Eri Ishikawa, Masatomo Takahashi, Akihiro Imamura, Hideharu Ishida, Federica Compostella, Hiroshi Kida, Atsushi Kumanogoh, Takeshi Bamba, Yoshihiro Izumi, Sho Yamasaki

{"title":"Identification of α-galactosylceramide as an endogenous mammalian antigen for iNKT cells.","authors":"Yuki Hosono, Noriyuki Tomiyasu, Hayato Kasai, Eri Ishikawa, Masatomo Takahashi, Akihiro Imamura, Hideharu Ishida, Federica Compostella, Hiroshi Kida, Atsushi Kumanogoh, Takeshi Bamba, Yoshihiro Izumi, Sho Yamasaki","doi":"10.1084/jem.20240728","DOIUrl":"10.1084/jem.20240728","url":null,"abstract":"Invariant natural killer T (iNKT) cells are unconventional T cells recognizing lipid antigens in a CD1d-restricted manner. Among these lipid antigens, α-galactosylceramide (α-GalCer), which was originally identified in marine sponges, is the most potent antigen. Although the presence of α-anomeric hexosylceramide and microbiota-derived branched α-GalCer is reported, antigenic α-GalCer has not been identified in mammals. Here, we developed a high-resolution separation and detection system, supercritical fluid chromatography tandem mass spectrometry (SFC/MS/MS), that can discriminate hexosylceramide diastereomers (α-GalCer, α-GlcCer, β-GalCer, or β-GlcCer). The B16 melanoma tumor cell line does not activate iNKT cells; however, ectopic expression of CD1d was sufficient to activate iNKT cells without adding antigens. B16 melanoma was unlikely to generate iNKT cell antigens; instead, antigen activity was detected in cell culture serum. Activity-based purification and SFC/MS/MS identified dihydrosphingosine-based saturated α-GalCer as an antigenic component in serum, bile, and lymphoid tissues. These results show the first evidence for the presence of potent antigenic α-GalCer in mammals.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 2","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

p38α-eIF6-Nsun2 axis promotes ILC3's rapid response to protect host from intestinal inflammation. p38α-eIF6-Nsun2 轴促进 ILC3 快速反应，保护宿主免受肠道炎症侵袭。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-26 DOI: 10.1084/jem.20240624

Jida Huang, Jing Zhang, Panwei Song, Jiaoyan Huang, Zi Yang, Jiahuai Han, Li Wu, Xiaohuan Guo

{"title":"p38α-eIF6-Nsun2 axis promotes ILC3's rapid response to protect host from intestinal inflammation.","authors":"Jida Huang, Jing Zhang, Panwei Song, Jiaoyan Huang, Zi Yang, Jiahuai Han, Li Wu, Xiaohuan Guo","doi":"10.1084/jem.20240624","DOIUrl":"10.1084/jem.20240624","url":null,"abstract":"Group 3 innate lymphoid cells (ILC3s) are important for maintaining gut homeostasis. Upon stimulation, ILC3s can rapidly produce cytokines to protect against infections and colitis. However, the regulation of ILC3 quick response is still unclear. Here, we find that eIF6 aggregates with Nsun2 and cytokine mRNA in ILC3s at steady state, which inhibits the methyltransferase activity of Nsun2 and the nuclear export of cytokine mRNA, resulting in the nuclear reservation of cytokine mRNA. Upon stimulation, phosphorylated p38α phosphorylates eIF6, which in turn releases Nsun2 activity, and promotes the nuclear export of cytokine mRNA and rapid cytokine production. Genetic disruption of p38α, Nsun2, or eIF6 in ILC3s influences the mRNA nuclear export and protein expression of the protective cytokines, thus leading to increased susceptibility to colitis. Together, our data identify a crucial role of the p38α-eIF6-Nsun2 axis in regulating rapid ILC3 immune response at the posttranscriptional level, which is critical for gut homeostasis maintenance and protection against gut inflammation.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma. 肿瘤相关的中性粒细胞减弱肝细胞癌的免疫敏感性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-05 DOI: 10.1084/jem.20241442

Jia Ming Nickolas Teo, Zhulin Chen, Weixin Chen, Rachael Julia Yuenyinn Tan, Qi Cao, Yingming Chu, Delin Ma, Liting Chen, Huajian Yu, Ka-Hei Lam, Terence Kin Wah Lee, Svetoslav Chakarov, Burkhard Becher, Ning Zhang, Zhao Li, Stephanie Ma, Ruidong Xue, Guang Sheng Ling

{"title":"Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma.","authors":"Jia Ming Nickolas Teo, Zhulin Chen, Weixin Chen, Rachael Julia Yuenyinn Tan, Qi Cao, Yingming Chu, Delin Ma, Liting Chen, Huajian Yu, Ka-Hei Lam, Terence Kin Wah Lee, Svetoslav Chakarov, Burkhard Becher, Ning Zhang, Zhao Li, Stephanie Ma, Ruidong Xue, Guang Sheng Ling","doi":"10.1084/jem.20241442","DOIUrl":"10.1084/jem.20241442","url":null,"abstract":"Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs affect metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) more than viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer. 缺氧与肺癌患者对免疫检查点抑制剂的获得性抵抗有关。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-25 DOI: 10.1084/jem.20231106

Camila Robles-Oteíza, Katherine Hastings, Jungmin Choi, Isabelle Sirois, Arvind Ravi, Francisco Expósito, Fernando de Miguel, James R Knight, Francesc López-Giráldez, Hyejin Choi, Nicholas D Socci, Taha Merghoub, Mark Awad, Gad Getz, Justin Gainor, Matthew D Hellmann, Étienne Caron, Susan M Kaech, Katerina Politi

{"title":"Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.","authors":"Camila Robles-Oteíza, Katherine Hastings, Jungmin Choi, Isabelle Sirois, Arvind Ravi, Francisco Expósito, Fernando de Miguel, James R Knight, Francesc López-Giráldez, Hyejin Choi, Nicholas D Socci, Taha Merghoub, Mark Awad, Gad Getz, Justin Gainor, Matthew D Hellmann, Étienne Caron, Susan M Kaech, Katerina Politi","doi":"10.1084/jem.20231106","DOIUrl":"10.1084/jem.20231106","url":null,"abstract":"Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency. ITPR3 的显性负变异会损害 T 细胞 Ca2+ 动力，导致联合免疫缺陷症。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-19 DOI: 10.1084/jem.20220979

Elena Blanco, Carme Camps, Sameer Bahal, Mohit D Kerai, Matteo P Ferla, Adam M Rochussen, Adam E Handel, Zainab M Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas M Keane, Sabrina Lizot, Maaike A A Kusters, Mildred A Iro, Sanjay V Patel, Emma C Morris, Siobhan O Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E Valdebenito, Grant S Stewart, Austen Worth, Stuart P Adams, Michael Duchen, Isabelle André, David J Adams, Giorgia Santili, Kimberly C Gilmour, Georg A Holländer, E Graham Davies, Jenny C Taylor, Gillian M Griffiths, Adrian J Thrasher, Fatima Dhalla, Alexandra Y Kreins

{"title":"Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.","authors":"Elena Blanco, Carme Camps, Sameer Bahal, Mohit D Kerai, Matteo P Ferla, Adam M Rochussen, Adam E Handel, Zainab M Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas M Keane, Sabrina Lizot, Maaike A A Kusters, Mildred A Iro, Sanjay V Patel, Emma C Morris, Siobhan O Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E Valdebenito, Grant S Stewart, Austen Worth, Stuart P Adams, Michael Duchen, Isabelle André, David J Adams, Giorgia Santili, Kimberly C Gilmour, Georg A Holländer, E Graham Davies, Jenny C Taylor, Gillian M Griffiths, Adrian J Thrasher, Fatima Dhalla, Alexandra Y Kreins","doi":"10.1084/jem.20220979","DOIUrl":"10.1084/jem.20220979","url":null,"abstract":"The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL. JNK1 抑制剂可靶向远端 B 细胞受体信号转导，克服 CLL 中 BTK 抑制剂的耐药性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-21 DOI: 10.1084/jem.20230681

Shifa Khaja Saleem, Sarah Decker, Sandra Kissel, Marcus Bauer, Dmitry Chernyakov, Daniela Bräuer-Hartmann, Konrad Aumann, Claudia Wickenhauser, Marco Herling, Oleksandra Skorobohatko, Nimitha Mathew, Cornelius Schmidt, Claudius Klein, Marie Follo, Christine Dierks

{"title":"JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL.","authors":"Shifa Khaja Saleem, Sarah Decker, Sandra Kissel, Marcus Bauer, Dmitry Chernyakov, Daniela Bräuer-Hartmann, Konrad Aumann, Claudia Wickenhauser, Marco Herling, Oleksandra Skorobohatko, Nimitha Mathew, Cornelius Schmidt, Claudius Klein, Marie Follo, Christine Dierks","doi":"10.1084/jem.20230681","DOIUrl":"10.1084/jem.20230681","url":null,"abstract":"Inhibition of the proximal B cell receptor (BCR) signaling pathway by BTK inhibitors is highly effective in the treatment of CLL, but drug resistance or intolerance occurs. Here, we investigated c-Jun N-terminal protein kinase 1 (JNK1) as an alternative drug target in the distal BCR pathway. JNK1 was preferentially overexpressed and activated in poor prognostic CLL with unmutated IGHV. Proximal BCR inhibition (BTK, PI3K, or SYK inhibitors) or SYK knockdown efficiently dephosphorylated JNK1, identifying JNK1 as a critical BCR downstream kinase in CLL. JNK1 inhibition induced apoptosis in primary CLL cells, resulting in the downregulation of BCL2, MCL1, and c-JUN. JNK1 inhibition in patient-derived CLL xenografted mice and Eµ-TCL1-tg mice prevented CLL progression, reduced splenic infiltration, and restored T cell function and normal hematopoiesis. JNK1 inhibitors even remained effective in ibrutinib refractory CLL. In conclusion, our study revealed JNK1 as a promising drug target in CLL downstream of the BCR, overcoming ibrutinib resistance, blocking the protective microenvironment, and improving CLL-specific immunosuppressive mechanisms.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human DBR1 deficiency impairs stress granule-dependent PKR antiviral immunity. 人类DBR1缺乏损害应激颗粒依赖性PKR抗病毒免疫。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-05 DOI: 10.1084/jem.20240010

Shuo Ru, Sisi Tang, Hui Xu, Jiahao Yin, Yan Guo, Liuping Song, Zhenyu Jin, Danyel Lee, Yi-Hao Chan, Xingyao Chen, Luke Buerer, William Fairbrother, Weidong Jia, Jean-Laurent Casanova, Shen-Ying Zhang, Daxing Gao

{"title":"Human DBR1 deficiency impairs stress granule-dependent PKR antiviral immunity.","authors":"Shuo Ru, Sisi Tang, Hui Xu, Jiahao Yin, Yan Guo, Liuping Song, Zhenyu Jin, Danyel Lee, Yi-Hao Chan, Xingyao Chen, Luke Buerer, William Fairbrother, Weidong Jia, Jean-Laurent Casanova, Shen-Ying Zhang, Daxing Gao","doi":"10.1084/jem.20240010","DOIUrl":"10.1084/jem.20240010","url":null,"abstract":"The molecular mechanism by which inborn errors of the human RNA lariat-debranching enzyme 1 (DBR1) underlie brainstem viral encephalitis is unknown. We show here that the accumulation of RNA lariats in human DBR1-deficient cells interferes with stress granule (SG) assembly, promoting the proteasome degradation of at least G3BP1 and G3BP2, two key components of SGs. In turn, impaired assembly of SGs, which normally recruit PKR, impairs PKR activation and activity against viruses, including HSV-1. Remarkably, the genetic ablation of PKR abolishes the corresponding antiviral effect of DBR1 in vitro. We also show that Dbr1Y17H/Y17H mice are susceptible to similar viral infections in vivo. Moreover, cells and brain samples from Dbr1Y17H/Y17H mice exhibit decreased G3BP1/2 expression and PKR phosphorylation. Thus, the debranching of RNA lariats by DBR1 permits G3BP1/2- and SG assembly-mediated PKR activation and cell-intrinsic antiviral immunity in mice and humans. DBR1-deficient patients are prone to viral disease because of intracellular lariat accumulation, which impairs G3BP1/2- and SG assembly-dependent PKR activation.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic and environmental risks for clonal hematopoiesis and cancer. 克隆造血和癌症的遗传和环境风险。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-12-03 DOI: 10.1084/jem.20230931

Stephanie Franco, Lucy A Godley

引用次数: 0