Mortality factor 4 like 1 protein mediates epithelial cell death in a mouse model of pneumonia.

Abstract

Unchecked epithelial cell death is fundamental to the pathogenesis of pneumonia. The recognition of unique signaling pathways that preserve epithelial cell viability may present new opportunities for interventional strategies. We describe that mortality factor 4 like 1 (Morf4l1), a protein involved in chromatin remodeling, is constitutively expressed at low levels in the lung because of its continuous degradation mediated by an orphan ubiquitin E3 ligase subunit, Fbxl18. Expression of Morf4l1 increases in humans with pneumonia and is up-regulated in lung epithelia after exposure to Pseudomonas aeruginosa or lipopolysaccharide. In a mouse model of pneumonia induced by P. aeruginosa, Morf4l1 is stabilized by acetylation that protects it from Fbxl18-mediated degradation. After P. aeruginosa infection of mice, overexpression of Morf4l1 resulted in lung epithelial cell death, whereas its depletion restored cell viability. Using in silico modeling and drug-target interaction studies, we identified that the U.S. Food and Drug Administration-approved thrombin inhibitor argatroban is a Morf4l1 antagonist. Argatroban inhibited Morf4l1-dependent histone acetylation, reduced its cytotoxicity, and improved survival of mice with experimental lung injury at doses that had no anticoagulant activity. These studies uncover a previously unrecognized biological mechanism whereby pathogens subvert cell viability by extending the life span of a cytotoxic host protein. Morf4l1 may be a potential molecular target for non-antibiotic pharmacotherapy during severe pulmonary infection.

• Authors: Chunbin Zou, Jin Li, Sheng Xiong, Yan Chen, Qin Wu, Xiuying Li, Nathaniel M Weathington, SeungHye Han, Courtney Snavely, Bill B Chen, Rama K Mallampalli
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 311 Pg. 311ra171 (Oct 28 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26511508 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• MORF4L1 protein, human
• Transcription Factors

Topics

• Animals
• Disease Models, Animal
• Epithelial Cells (metabolism)
• Humans
• In Vitro Techniques
• Lung (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Pneumonia (metabolism, microbiology)
• Pseudomonas Infections (metabolism)
• Pseudomonas aeruginosa (pathogenicity)
• Transcription Factors (genetics, metabolism)