An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth
Abstract Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an ‘organiser’ of protein networks to generate a new or different biological effect from that identified in EV‐producing cells has never been demonstrated. Here, as a proof‐of‐concept, we...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-02-01
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| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jev2.12307 |
| _version_ | 1797895467614339072 |
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| author | Mukesh K. Sriwastva Yun Teng Jingyao Mu Fangyi Xu Anil Kumar Kumaran Sundaram Rajiv Kumar Malhotra Qingbo Xu Joshua L. Hood Lifeng Zhang Jun Yan Michael L. Merchant Juw Won Park Gerald W. Dryden Nejat K. Egilmez Huang‐Ge Zhang |
| author_facet | Mukesh K. Sriwastva Yun Teng Jingyao Mu Fangyi Xu Anil Kumar Kumaran Sundaram Rajiv Kumar Malhotra Qingbo Xu Joshua L. Hood Lifeng Zhang Jun Yan Michael L. Merchant Juw Won Park Gerald W. Dryden Nejat K. Egilmez Huang‐Ge Zhang |
| author_sort | Mukesh K. Sriwastva |
| collection | DOAJ |
| description | Abstract Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an ‘organiser’ of protein networks to generate a new or different biological effect from that identified in EV‐producing cells has never been demonstrated. Here, as a proof‐of‐concept, we demonstrate that EV‐G12D‐mutant KRAS serves as a leader that forms a protein complex and promotes lung inflammation and tumour growth via the Fn1/IL‐17A/FGF21 axis. Mechanistically, in contrast to cytosol derived G12D‐mutant KRAS complex from EVs‐producing cells, EV‐G12D‐mutant KRAS interacts with a group of extracellular vesicular factors via fibronectin‐1 (Fn1), which drives the activation of the IL‐17A/FGF21 inflammation pathway in EV recipient cells. We show that: (i), depletion of EV‐Fn1 leads to a reduction of a number of inflammatory cytokines including IL‐17A; (ii) induction of IL‐17A promotes lung inflammation, which in turn leads to IL‐17A mediated induction of FGF21 in the lung; and (iii) EV‐G12D‐mutant KRAS complex mediated lung inflammation is abrogated in IL‐17 receptor KO mice. These findings establish a new concept in EV function with potential implications for novel therapeutic interventions in EV‐mediated disease processes. |
| first_indexed | 2024-04-10T07:26:11Z |
| format | Article |
| id | doaj.art-33c5cd4cf6cb4bf493fc823ff60c3791 |
| institution | Directory Open Access Journal |
| issn | 2001-3078 |
| language | English |
| last_indexed | 2024-04-10T07:26:11Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj.art-33c5cd4cf6cb4bf493fc823ff60c37912023-02-24T05:50:30ZengWileyJournal of Extracellular Vesicles2001-30782023-02-01122n/an/a10.1002/jev2.12307An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growthMukesh K. Sriwastva0Yun Teng1Jingyao Mu2Fangyi Xu3Anil Kumar4Kumaran Sundaram5Rajiv Kumar Malhotra6Qingbo Xu7Joshua L. Hood8Lifeng Zhang9Jun Yan10Michael L. Merchant11Juw Won Park12Gerald W. Dryden13Nejat K. Egilmez14Huang‐Ge Zhang15Brown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USADepartment of Pharmacology and Toxicology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USAKidney Disease Program and Clinical Proteomics Center University of Louisville Louisville Kentucky USAKBRIN Bioinformatics Core University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USABrown Cancer Center, Department of Microbiology & Immunology University of Louisville Louisville Kentucky USAAbstract Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an ‘organiser’ of protein networks to generate a new or different biological effect from that identified in EV‐producing cells has never been demonstrated. Here, as a proof‐of‐concept, we demonstrate that EV‐G12D‐mutant KRAS serves as a leader that forms a protein complex and promotes lung inflammation and tumour growth via the Fn1/IL‐17A/FGF21 axis. Mechanistically, in contrast to cytosol derived G12D‐mutant KRAS complex from EVs‐producing cells, EV‐G12D‐mutant KRAS interacts with a group of extracellular vesicular factors via fibronectin‐1 (Fn1), which drives the activation of the IL‐17A/FGF21 inflammation pathway in EV recipient cells. We show that: (i), depletion of EV‐Fn1 leads to a reduction of a number of inflammatory cytokines including IL‐17A; (ii) induction of IL‐17A promotes lung inflammation, which in turn leads to IL‐17A mediated induction of FGF21 in the lung; and (iii) EV‐G12D‐mutant KRAS complex mediated lung inflammation is abrogated in IL‐17 receptor KO mice. These findings establish a new concept in EV function with potential implications for novel therapeutic interventions in EV‐mediated disease processes.https://doi.org/10.1002/jev2.12307extracellular vesicles (EV)fibronectin (Fn1)inflammationKRASlung tumourplant lipid liposomes |
| spellingShingle | Mukesh K. Sriwastva Yun Teng Jingyao Mu Fangyi Xu Anil Kumar Kumaran Sundaram Rajiv Kumar Malhotra Qingbo Xu Joshua L. Hood Lifeng Zhang Jun Yan Michael L. Merchant Juw Won Park Gerald W. Dryden Nejat K. Egilmez Huang‐Ge Zhang An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth Journal of Extracellular Vesicles extracellular vesicles (EV) fibronectin (Fn1) inflammation KRAS lung tumour plant lipid liposomes |
| title | An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth |
| title_full | An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth |
| title_fullStr | An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth |
| title_full_unstemmed | An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth |
| title_short | An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth |
| title_sort | extracellular vesicular mutant kras associated protein complex promotes lung inflammation and tumor growth |
| topic | extracellular vesicles (EV) fibronectin (Fn1) inflammation KRAS lung tumour plant lipid liposomes |
| url | https://doi.org/10.1002/jev2.12307 |
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