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c-Abl-TWIST1 Epigenetically Dysregulate Inflammatory Responses during Mycobacterial Infection by Co-Regulating Bone Morphogenesis Protein and miR27a

Mahadik, Kasturi and Prakhar, Praveen and Rajmani, R S and Singh, Amit and Balaji, Kithiganahalli Narayanaswamy (2018) c-Abl-TWIST1 Epigenetically Dysregulate Inflammatory Responses during Mycobacterial Infection by Co-Regulating Bone Morphogenesis Protein and miR27a. In: FRONTIERS IN IMMUNOLOGY, 9 .

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Official URL: http://dx.doi.org/10.3389/fimmu.2018.00085

Abstract

Mycobacteria propelled modulation of host responses is of considerable interest in the face of emerging drug resistance. Although it is known that Abl tyrosine kinases affect entry and persistence of mycobacteria, mechanisms that couple c-Abl to proximal signaling pathways during immunity are poorly understood. Loss-of-function of c-Abl through Imatinib, in a mouse model of tuberculosis or RNA interference, identified bone morphogenesis protein (BMP) signaling as its cellular target. We demonstrate that c-Abl promotes mycobacterial survival through epigenetic modification brought about by KAT5-TWIST1 at Bmp loci. c-Abl-BMP signaling deregulated iNOS, aggravating the inflammatory balance. Interestingly, BMP signaling was observed to have far-reaching effects on host immunity, as it attenuated TLR3 pathway by engaging miR27a. Significantly, these events were largely mediated via WhiB3 and DosR/S/T but not SecA signaling pathway of mycobacteria. Our findings suggest molecular mechanisms of host pathways hijacked by mycobacteria and expand our understanding of c-Abl inhibitors in potentiating innate immune responses.

Item Type: Journal Article
Additional Information: Copy right for this article belong to the FRONTIERS MEDIA SA, PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Division of Biological Sciences > Centre for Infectious Disease Research
Depositing User: Id for Latest eprints
Date Deposited: 02 Mar 2018 15:04
Last Modified: 02 Mar 2018 15:04
URI: http://eprints.iisc.ac.in/id/eprint/58937

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