Journal of Experimental Medicine最新文献_第6页

CCDC134 controls TLR biogenesis through the ER chaperone Gp96. CCDC134通过ER伴侣Gp96控制TLR的生物发生。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-03-03 Epub Date: 2024-12-10 DOI: 10.1084/jem.20240825

Léa Bernaleau, Michaela Drobek, Fenja Blank, Philipp Walch, Maeva Delacrétaz, Ales Drobek, Marta Monguió-Tortajada, Petr Broz, Olivia Majer, Manuele Rebsamen

{"title":"CCDC134 controls TLR biogenesis through the ER chaperone Gp96.","authors":"Léa Bernaleau, Michaela Drobek, Fenja Blank, Philipp Walch, Maeva Delacrétaz, Ales Drobek, Marta Monguió-Tortajada, Petr Broz, Olivia Majer, Manuele Rebsamen","doi":"10.1084/jem.20240825","DOIUrl":"10.1084/jem.20240825","url":null,"abstract":"Toll-like receptors (TLRs) are central to initiate immune responses against invading pathogens. To ensure host defense while avoiding aberrant activation leading to pathogenic inflammation and autoimmune diseases, TLRs are tightly controlled by multilevel regulatory mechanisms. Through a loss-of-function genetic screen in a reporter cell line engineered to undergo cell death upon TLR7-induced IRF5 activation, we identified here CCDC134 as an essential factor for TLR responses. CCDC134 deficiency impaired endolysosomal TLR-induced NF-κB, MAPK, and IRF5 activation, as well as downstream production of proinflammatory cytokines and type I interferons. We further demonstrated that CCDC134 is an endoplasmic reticulum (ER)-resident interactor of Gp96 (HSP90B1/Grp94), an ER chaperone essential for folding and trafficking of plasma membrane and endolysosomal TLRs. CCDC134 controlled Gp96 stability as its loss led to Gp96 hyperglycosylation and ER-associated protein degradation (ERAD)-mediated clearance. Accordingly, CCDC134 deficiency impaired the folding, maturation, and trafficking of TLRs, resulting in blunted inflammatory responses upon stimulation. Altogether, this study reveals CCDC134 as a central regulator of the chaperone Gp96, thereby controlling TLR biogenesis and responses.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 3","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801074","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

Mechanosensing regulates pDC activation in the skin through NRF2 activation. 机械感应通过NRF2激活调节皮肤中pDC的激活。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-03-03 Epub Date: 2024-12-13 DOI: 10.1084/jem.20240852

Vidyanath Chaudhary, Bikash Mishra, Marie Dominique Ah Kioon, Yong Du, Lionel B Ivashkiv, Mary K Crow, Franck J Barrat

{"title":"Mechanosensing regulates pDC activation in the skin through NRF2 activation.","authors":"Vidyanath Chaudhary, Bikash Mishra, Marie Dominique Ah Kioon, Yong Du, Lionel B Ivashkiv, Mary K Crow, Franck J Barrat","doi":"10.1084/jem.20240852","DOIUrl":"10.1084/jem.20240852","url":null,"abstract":"Plasmacytoid DCs (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I), and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness inhibits the production of IFN-I by pDCs. Mechanistically, mechanosensing activates stress pathways including NRF2, which induces the pentose phosphate pathway and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 activity in vivo controlled the pDC response, leading to resolution or chronic induction of IFN-I in the skin. In systemic sclerosis (SSc) patients, although NRF2 was induced in skin-infiltrating pDCs, as compared with blood pDCs, the IFN response was maintained. We observed that CXCL4, a profibrotic chemokine elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 3","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818249","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

pDCs, type 1 IFN, and the female predileXion of SSc. pDCs、1型IFN与SSc的女性倾向。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-03-03 Epub Date: 2025-01-17 DOI: 10.1084/jem.20242284

Nikhil Jiwrajka, Montserrat C Anguera

引用次数: 0

PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers. ptpn23依赖性激活PI3KC2α是braf突变型癌症的治疗易感性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-03-03 Epub Date: 2025-01-22 DOI: 10.1084/jem.20241147

Ying He, Wei Li, Meiling Zhang, Hui Wang, Peilu Lin, Ying Yu, Bin Huang, Meng Hao, Jianuo He, Weiyao Kong, Dan Luo, Tengteng Xu, Jiaqi Wang, Ying Huang, Qinwen Zhao, Ying Liu, Jie Zhang, Yong Nian, Lei Zhang, Bo Zhu, Chengqian Yin

{"title":"PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers.","authors":"Ying He, Wei Li, Meiling Zhang, Hui Wang, Peilu Lin, Ying Yu, Bin Huang, Meng Hao, Jianuo He, Weiyao Kong, Dan Luo, Tengteng Xu, Jiaqi Wang, Ying Huang, Qinwen Zhao, Ying Liu, Jie Zhang, Yong Nian, Lei Zhang, Bo Zhu, Chengqian Yin","doi":"10.1084/jem.20241147","DOIUrl":"10.1084/jem.20241147","url":null,"abstract":"BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non-receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells. Silencing PTPN23 selectively kills BRAF-mutant melanoma cells but not those with wild-type BRAF. Mechanistically, PTPN23, a catalytically inactive phosphatase, intriguingly induces WNK3-mediated phosphorylation of phosphoinositide 3-kinase class II alpha (PI3KC2α) at serine 329, enhancing its catalytic activity. This activation promotes production of PI(3,4)P2 and subsequent AKT2 activation at endosomes to support cell survival. Genetic or pharmacological targeting of the PTPN23-PI3KC2α-AKT2 signaling axis, alone or in combination with BRAF inhibitors, effectively inhibits the growth of BRAF-mutant melanoma and other cancers in vitro and in vivo. We also demonstrate that melanocyte-specific knockout of PTPN23 significantly inhibits BRAFV600E-driven melanomagenesis. Altogether, our findings demonstrate that targeting PTPN23/PI3KC2α offers a new and viable therapeutic strategy for BRAF-mutant cancers.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 3","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006477","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

Lymphatic transport in anti-tumor immunity and metastasis.

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-03-03 Epub Date: 2025-02-19 DOI: 10.1084/jem.20231954

Mengzhu Sun, Julien Angelillo, Stéphanie Hugues

引用次数: 0

No added sugar: CCDC134 stabilizes ER chaperone Gp96 for TLR biogenesis.

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-03-03 Epub Date: 2025-02-05 DOI: 10.1084/jem.20242285

Antje Blumenthal, Leslie C Domínguez Cadena

引用次数: 0

The α glycolipid rules the NKT cell TCR. α糖脂控制NKT细胞TCR。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-02-03 Epub Date: 2024-12-23 DOI: 10.1084/jem.20242099

Mitchell Kronenberg, Gabriel Ascui

引用次数: 0

Natural antibodies to polysaccharide capsules enable Kupffer cells to capture invading bacteria in the liver sinusoids. 多糖胶囊的天然抗体使库普弗细胞能够捕获肝窦中的入侵细菌。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-02-03 Epub Date: 2024-12-24 DOI: 10.1084/jem.20240735

Xianbin Tian, Yanni Liu, Kun Zhu, Haoran An, Jie Feng, Linqi Zhang, Jing-Ren Zhang

{"title":"Natural antibodies to polysaccharide capsules enable Kupffer cells to capture invading bacteria in the liver sinusoids.","authors":"Xianbin Tian, Yanni Liu, Kun Zhu, Haoran An, Jie Feng, Linqi Zhang, Jing-Ren Zhang","doi":"10.1084/jem.20240735","DOIUrl":"10.1084/jem.20240735","url":null,"abstract":"The interception of blood-borne bacteria in the liver defines the outcomes of invasive bacterial infections, but the mechanisms of this antibacterial immunity are not fully understood. This study shows that natural antibodies (nAbs) to capsules enable liver macrophage Kupffer cells (KCs) to rapidly capture and kill blood-borne encapsulated bacteria in mice. Affinity pulldown with serotype-10A capsular polysaccharides (CPS10A) of Streptococcus pneumoniae (Spn10A) led to the identification of CPS10A-binding nAbs in serum. The CPS10A-antibody interaction enabled KCs to capture Spn10A bacteria from the bloodstream, in part through complement receptors on KCs. The nAbs were found to recognize the β1-6-linked galactose branch of CPS10A and similar moieties of serotype-39 S. pneumoniae and serotype-K50 Klebsiella pneumoniae capsules. More importantly, the nAbs empowered KCs to capture serotype-39 S. pneumoniae and serotype-K50 K. pneumoniae in the liver. Collectively, our data have revealed a highly effective immune function of nAb against encapsulated bacteria and emphasize the concept of treating septic encapsulated bacterial diseases with monoclonal antibodies.","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/PMC11668174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882146","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

Cigarette smoke components modulate the MR1-MAIT axis. 香烟烟雾成分调节MR1-MAIT轴。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-02-03 Epub Date: 2025-01-17 DOI: 10.1084/jem.20240896

Wael Awad, Jemma R Mayall, Weijun Xu, Matt D Johansen, Timothy Patton, Xin Yi Lim, Izabela Galvao, Lauren J Howson, Alexandra C Brown, Tatt Jhong Haw, Chantal Donovan, Shatarupa Das, Gesa J Albers, Tsung-Yu Pai, Elinor Hortle, Caitlin M Gillis, Nicole G Hansbro, Jay C Horvat, Ligong Liu, Jeffrey Y W Mak, James McCluskey, David P Fairlie, Alexandra J Corbett, Philip M Hansbro, Jamie Rossjohn

{"title":"Cigarette smoke components modulate the MR1-MAIT axis.","authors":"Wael Awad, Jemma R Mayall, Weijun Xu, Matt D Johansen, Timothy Patton, Xin Yi Lim, Izabela Galvao, Lauren J Howson, Alexandra C Brown, Tatt Jhong Haw, Chantal Donovan, Shatarupa Das, Gesa J Albers, Tsung-Yu Pai, Elinor Hortle, Caitlin M Gillis, Nicole G Hansbro, Jay C Horvat, Ligong Liu, Jeffrey Y W Mak, James McCluskey, David P Fairlie, Alexandra J Corbett, Philip M Hansbro, Jamie Rossjohn","doi":"10.1084/jem.20240896","DOIUrl":"https://doi.org/10.1084/jem.20240896","url":null,"abstract":"Tobacco smoking is prevalent across the world and causes numerous diseases. Cigarette smoke (CS) compromises immunity, yet little is known of the components of CS that impact T cell function. MR1 is a ubiquitous molecule that presents bacterial metabolites to MAIT cells, which are highly abundant in the lungs. Using in silico, cellular, and biochemical approaches, we identified components of CS that bind MR1 and impact MR1 cell surface expression. Compounds, including nicotinaldehyde, phenylpropanoid, and benzaldehyde-related scaffolds, bound within the A' pocket of MR1. CS inhibited MAIT cell activation, ex vivo, via TCR-dependent and TCR-independent mechanisms. Chronic CS exposure altered MAIT cell phenotype and function and attenuated MAIT cell responses to influenza A virus infection in vivo. MR1-deficient mice were partially protected from the development of chronic obstructive pulmonary disease (COPD) features that were associated with CS exposure. Thus, CS can impair MAIT cell function by diverse mechanisms, and potentially contribute to infection susceptibility and disease exacerbations.","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/PMC11740918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006488","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

Dual role of vascular endothelial growth factor-C in post-stroke recovery. 血管内皮生长因子- c在脑卒中后恢复中的双重作用。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-02-03 Epub Date: 2024-12-12 DOI: 10.1084/jem.20231816

Yun Hwa Choi, Martin Hsu, Collin Laaker, Jenna Port, Kristóf G Kovács, Melinda Herbath, Heeyoon Yang, Peter Cismaru, Alexis M Johnson, Bailey Spellman, Kelsey Wigand, Matyas Sandor, Zsuzsanna Fabry

{"title":"Dual role of vascular endothelial growth factor-C in post-stroke recovery.","authors":"Yun Hwa Choi, Martin Hsu, Collin Laaker, Jenna Port, Kristóf G Kovács, Melinda Herbath, Heeyoon Yang, Peter Cismaru, Alexis M Johnson, Bailey Spellman, Kelsey Wigand, Matyas Sandor, Zsuzsanna Fabry","doi":"10.1084/jem.20231816","DOIUrl":"10.1084/jem.20231816","url":null,"abstract":"Cerebrospinal fluid (CSF), antigens, and antigen-presenting cells drain from the central nervous system (CNS) into lymphatic vessels near the cribriform plate and dura, yet the role of these vessels during stroke is unclear. Using a mouse model of ischemic stroke, transient middle cerebral artery occlusion (tMCAO), we demonstrate stroke-induced lymphangiogenesis near the cribriform plate, peaking at day 7 and regressing by day 14. Lymphangiogenesis is restricted to the cribriform plate and deep cervical lymph nodes and is regulated by VEGF-C/VEGFR-3 signaling. The use of a VEGFR-3 inhibitor prevented lymphangiogenesis and led to improved stroke outcomes at earlier time points, with no effects at later time points. VEGF-C delivery after tMCAO did not further increase post-stroke lymphangiogenesis, but instead induced larger brain infarcts. Our data support the damaging role of VEGF-C acutely and a pro-angiogenic role chronically. This nuanced understanding of VEGFR-3 and VEGF-C in stroke pathology advises caution regarding therapeutic VEGF-C use in stroke.","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/PMC11636551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813288","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