Mycobacterium tuberculosis, the pathogen that causes tuberculosis, exhibits complex host-pathogen interactions. Pattern recognition receptors and their downstream signaling pathways play crucial roles in determining the outcome of infection. In particular, the scaffold protein beta-arrestin 2 mediates downstream signaling of G protein-coupled receptors. However, the role of beta-arrestin 2 in conferring immunity against M. tuberculosis has not yet been explored. We found that beta-arrestin 2 was upregulated in the lesioned regions of lung tissues in patients with tuberculosis. M. tuberculosis infection upregulated beta-arrestin 2 expression in human macrophages, and silencing of beta-arrestin 2 significantly enhanced bactericidal activity by enhancing the expression of proinflammatory cytokines such as TNF-alpha. beta-Arrestin 2 was shown to inhibit the activation of the TLR2/ERK1/2 pathway and its transcriptional regulation activity upon M. tuberculosis infection. Furthermore, beta-arrestin 2 transcriptionally regulates TNF-alpha by binding to CREB1. These observations revealed that the upregulation of beta-arrestin 2 is critical for M. tuberculosis to escape immune surveillance through an unknown mechanism. Our research offers a novel interference modality to enhance the immune response against tuberculosis by targeting beta-arrestin 2 to modulate the TLR2-beta-arrestin 2-ERK1/2-CREB1-TNF-alpha regulatory axis.
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