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Human IL10 gene repression by Rev-erbα ameliorates Mycobacterium tuberculosis clearance.

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Human IL10 gene repression by Rev-erbα ameliorates Mycobacterium tuberculosis clearance.
 
Creator Chandra, Vemika
Mahajan, Sahil
Saini, Ankita
Dkhar, Hedwin K
Nanduri, Ravikanth
Raj, Ella B
Kumar, Ashwani
Gupta, Pawan
 
Description Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erbα is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erbα in monocytes and macrophages. The nuclear localization of Rev-erbα in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erbα elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erbα overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erbα binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erbα bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.
 
Publisher Baltimore, MD : American Society for Biochemistry and Molecular Biology
 
Date 2013-04-12
 
Type Article
NonPeerReviewed
 
Relation http://www.jbc.org/content/288/15/10692.long
http://crdd.osdd.net/open/1623/
 
Identifier Chandra, Vemika and Mahajan, Sahil and Saini, Ankita and Dkhar, Hedwin K and Nanduri, Ravikanth and Raj, Ella B and Kumar, Ashwani and Gupta, Pawan (2013) Human IL10 gene repression by Rev-erbα ameliorates Mycobacterium tuberculosis clearance. The Journal of biological chemistry, 288 (15). pp. 10692-702. ISSN 1083-351X