H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Dezhi Zhao, Qian Zhang, Yiqi Liu, Xia Li, Kai Zhao, Yuanyuan Ding, Zhiqing Li, Qicong Shen, Chunmei Wang, Nan Li, Xuetao Cao
The H3K4me3 demethylase Kdm5a regulates gene transcription and is implicated in carcinogenesis. However, the role of Kdm5a in innate immune response remains poorly understood. Here, we demonstrate that Kdm5a deficiency impairs activation of natural killer (NK) cells, with decreased IFN-γ production. Accordingly, Kdm5a^−/− mice are highly susceptible to Listeria monocytogenes (Lm) infection. During NK cell activation, loss of Kdm5a profoundly impairs phosphorylation and nuclear localization of STAT4, along with increased expression of suppressor of cytokine signaling 1 (SOCS1). Mechanistic studies reveal that Kdm5a associates with p50 and binds to the Socs1 promoter region in resting NK cells, leading to a substantial decrease in H3K4me3 modification and repressive chromatin configuration at the Socs1 promoter. Thus, Kdm5a is required for priming activation of NK cells by suppressing the suppressor, SOCS1. Our study provides insights into the epigenetic regulation of innate immune response of NK cells.

Graphical abstract

Teaser

Zhao et al. show that the H3K4me3 demethylase Kdm5a is recruited to the SOCS1 promoter by p50 to maintain a repressive chromatin configuration. Kdm5a-mediated suppression of SOCS1 is required for NK cell activation and initiation of innate immune responses to infection. These results reveal a role for histone demethylation in NK cell activation.


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