An extracellular vesicular mutant KRAS‐associated protein complex promotes lung inflammation and tumor growth. Issue 2 (8th February 2023)

• Record Type: Journal Article
• Authors: Sriwastva, Mukesh K.; Teng, Yun; Mu, Jingyao; Xu, Fangyi; Kumar, Anil; Sundaram, Kumaran; Malhotra, Rajiv Kumar; Xu, Qingbo; Hood, Joshua L.; Zhang, Lifeng; Yan, Jun; Merchant, Michael L.; Park, Juw Won; Dryden, Gerald W.; Egilmez, Nejat K.; Zhang, Huang‐Ge
• Is Part Of: Journal of extracellular vesicles. Volume 12:Issue 2(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-08
• Subjects: extracellular vesicles (EV) -- fibronectin (Fn1) -- inflammation -- KRAS -- lung tumour -- plant lipid liposomes -- Protein networks; Cells -- Mechanical properties -- Periodicals; Transport Vesicles; Cells -- Mechanical properties; Periodicals; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 571.63
• DOI: 10.1002/jev2.12307
• Languages: English
• ISSNs: 2001-3078

Abstract

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.