Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model
Lu, Lu (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Wei, RanLei (Sichuan University. Center of Precision Medicine)
Prats-Ejarque, Guillem (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Goetz, Maria (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Wang, Gang (Sichuan University. Center of Precision Medicine)
Torrent, Marc (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Boix, Ester (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2020
Resum:	The human RNase3 is a member of the RNaseA superfamily involved in host immunity. RNase3 is expressed by leukocytes and shows broad-spectrum antimicrobial activity. Together with a direct antimicrobial action, RNase3 exhibits immunomodulatory properties. Here, we have analysed the transcriptome of macrophages exposed to the wild-type protein and a catalytic-defective mutant (RNase3-H15A). The analysis of differently expressed genes (DEGs) in treated THP1-derived macrophages highlighted a common pro-inflammatory "core-response" independent of the protein ribonucleolytic activity. Network analysis identified the epidermal growth factor receptor (EGFR) as the main central regulatory protein. Expression of selected DEGs and MAPK phosphorylation were inhibited by an anti-EGFR antibody. Structural analysis suggested that RNase3 activates the EGFR pathway by direct interaction with the receptor. Besides, we identified a subset of DEGs related to the protein ribonucleolytic activity, characteristic of virus infection response. Transcriptome analysis revealed an early pro-inflammatory response, not associated to the protein catalytic activity, followed by a late activation in a ribonucleolyticdependent manner. Next, we demonstrated that overexpression of macrophage endogenous RNase3 protects the cells against infection by Mycobacterium aurum and the human respiratory syncytial virus. Comparison of cell infection profiles in the presence of Erlotinib, an EGFR inhibitor, revealed that the receptor activation is required for the antibacterial but not for the antiviral protein action. Moreover, the DEGs related and unrelated to the protein catalytic activity are associated to the immune response to bacterial and viral infection, respectively. We conclude that RNase3 modulates the macrophage defence against infection in both catalytic-dependent and independent manners.
Ajuts:	Ministerio de Economía y Competitividad SAF2015-66007P Agencia Estatal de Investigación PID2019-106123GB-I00
Nota:	Altres ajuts: Fundació Marató TV3 [20180310]
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Ribonucleases ; Host defence ; EGFR ; Infection ; Mycobacterium aurum ; Respiratory syncytial virus ; Transcriptome
Publicat a:	Cellular and molecular life sciences, Vol. 78 (November 2020) , p. 2963-2985, ISSN 1420-9071

DOI: 10.1007/s00018-020-03695-5
PMID: 33226440

23 p, 6.4 MB

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