Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia

Yandong Lai; Xiuying Li; Tiao Li; Toru Nyunoya; Kong Chen; Georgios D Kitsios; Seyed Mehdi Nouraie; Yingze Zhang; Bryan J McVerry; Janet S Lee; Rama K Mallampalli; Chunbin Zou

doi:10.1038/s41419-021-04115-7

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Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia

Journal article

Peer reviewed

Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia

Yandong Lai, Xiuying Li, Tiao Li, Toru Nyunoya, Kong Chen, Georgios D Kitsios, Seyed Mehdi Nouraie, Yingze Zhang, Bryan J McVerry, Janet S Lee, …

Cell death & disease, Vol.12(9), pp.828-11

09/03/2021

DOI: 10.1038/s41419-021-04115-7

PMID: 34480022

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Abstract

Lung epithelial cell death is a prominent feature of acute lung injury and acute respiratory distress syndrome (ALI/ARDS), which results from severe pulmonary infection leading to respiratory failure. Multiple mechanisms are believed to contribute to the death of epithelia; however, limited data propose a role for epigenetic modifiers. In this study, we report that a chromatin modulator protein arginine N-methyltransferase 4/coactivator-associated arginine methyltransferase 1 (PRMT4/CARM1) is elevated in human lung tissues with pneumonia and in experimental lung injury models. Here PRMT4 is normally targeted for its degradation by an E3 ubiquitin ligase, SCF , that interacts with PRMT4 via a phosphodegron to ubiquitinate the chromatin modulator at K228 leading to its proteasomal degradation. Bacterial-derived endotoxin reduced levels of SCF thus increasing PRMT4 cellular concentrations linked to epithelial cell death. Elevated PRMT4 protein caused substantial epithelial cell death via caspase 3-mediated cell death signaling, and depletion of PRMT4 abolished LPS-mediated epithelial cell death both in cellular and murine injury models. These findings implicate a unique molecular interaction between SCF and PRMT4 and its regulation by endotoxin that impacts the life span of lung epithelia, which may play a key role in the pathobiology of tissue injury observed during critical respiratory illness.

Acute Lung Injury - enzymology

Acute Lung Injury - pathology

Animals

Caspase 3 - metabolism

Cell Death - drug effects

Cell Line

Endotoxins - toxicity

Enzyme Activation - drug effects

Enzyme Stability - drug effects

Epithelial Cells - drug effects

Epithelial Cells - enzymology

Epithelial Cells - pathology

F-Box Proteins - metabolism

Humans

Lung - pathology

Lysine - metabolism

Mice

Models, Biological

Phosphorylation - drug effects

Proteasome Endopeptidase Complex - metabolism

Protein-Arginine N-Methyltransferases - metabolism

Proteolysis - drug effects

Ubiquitin - metabolism

Ubiquitination - drug effects

Details

Title: Subtitle: Endotoxin stabilizes protein arginine methyltransferase 4 (PRMT4) protein triggering death of lung epithelia
Creators: Yandong Lai - University of Pittsburgh
Xiuying Li - VA Pittsburgh Healthcare System
Tiao Li - University of Pittsburgh
Toru Nyunoya - University of Pittsburgh
Kong Chen - University of Pittsburgh
Georgios D Kitsios - University of Pittsburgh
Seyed Mehdi Nouraie - University of Pittsburgh
Yingze Zhang - University of Pittsburgh
Bryan J McVerry - University of Pittsburgh
Janet S Lee - University of Pittsburgh
Rama K Mallampalli - University of Pittsburgh
Chunbin Zou - University of Pittsburgh
Resource Type: Journal article
Publication Details: Cell death & disease, Vol.12(9), pp.828-11
DOI: 10.1038/s41419-021-04115-7
PMID: 34480022
ISSN: 2041-4889
eISSN: 2041-4889
Grant note: R01 HL142997 / NHLBI NIH HHS R01 HL097376 / NHLBI NIH HHS R01 HL096376 / NHLBI NIH HHS HL142084 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01 HL098174 / NHLBI NIH HHS R01 HL142084 / NHLBI NIH HHS R01 HL125435 / NHLBI NIH HHS R01 HL149719 / NHLBI NIH HHS R01 HL126234 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) 5I01CX000105-06 / U.S. Department of Veterans Affairs (Department of Veterans Affairs)
Language: English
Date published: 09/03/2021
Academic Unit: Internal Medicine
Record Identifier: 9985214104302771

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