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The deubiquitinase UCHL3 mediates p300-dependent chemokine signaling in alveolar type II cells to promote pulmonary fibrosis

Authors
 Soo Yeon Lee  ;  Soo-Yeon Park  ;  Seung-Hyun Lee  ;  Hyunsik Kim  ;  Jae-Hwan Kwon  ;  Jung-Yoon Yoo  ;  Kyunggon Kim  ;  Moo Suk Park  ;  Chun Geun Lee  ;  Jack A Elias  ;  Myung Hyun Sohn  ;  Hyo Sup Shim  ;  Ho-Geun Yoon 
Citation
 EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.55(8) : 1795-1805, 2023-08 
Journal Title
EXPERIMENTAL AND MOLECULAR MEDICINE
ISSN
 1226-3613 
Issue Date
2023-08
MeSH
Alveolar Epithelial Cells* ; Animals ; Chemokine CCL2 / genetics ; Deubiquitinating Enzymes ; E1A-Associated p300 Protein ; Humans ; Idiopathic Pulmonary Fibrosis* / genetics ; Lung ; Mice ; Ubiquitin Thiolesterase* / metabolism
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal, fibrotic, interstitial lung disease of unknown cause. Despite extensive studies, the underlying mechanisms of IPF development remain unknown. Here, we found that p300 was upregulated in multiple epithelial cells in lung samples from patients with IPF and mouse models of lung fibrosis. Lung fibrosis was significantly diminished by the alveolar type II (ATII) cell-specific deletion of the p300 gene. Moreover, we found that ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of p300 led to the transcriptional activation of the chemokines Ccl2, Ccl7, and Ccl12 through the cooperative action of p300 and C/EBPβ, which consequently promoted M2 macrophage polarization. Selective blockade of p300 activity in ATII cells resulted in the reprogramming of M2 macrophages into antifibrotic macrophages. These findings demonstrate a pivotal role for p300 in the development of lung fibrosis and suggest that p300 could serve as a promising target for IPF treatment.

© 2023. The Author(s).
Files in This Item:
T202305196.pdf Download
DOI
10.1038/s12276-023-01066-1
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Park, Moo Suk(박무석) ORCID logo https://orcid.org/0000-0003-0820-7615
Park, Soo Yeon(박수연) ORCID logo https://orcid.org/0000-0003-3743-9554
Sohn, Myung Hyun(손명현) ORCID logo https://orcid.org/0000-0002-2478-487X
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
Lee, Soo Yeon(이수연)
Lee, Seung Hyun(이승현) ORCID logo https://orcid.org/0000-0001-7549-9430
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/196362
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