Toxin-antitoxin loci regulate adaptive responses to stresses associated with the host environment and drug exposure. Phylogenomic studies have shown that Mycobacterium tuberculosis encodes a naturally expanded type II toxin-antitoxin system, including ParDE/RelBE superfamily members. Type II toxins are presumably regulated exclusively through protein–protein interactions with type II antitoxins. However, experimental observations in M. tuberculosis indicated that additional control mechanisms regulate RelBE2 type II loci under host-associated stress conditions. Herein, we describe for the first time a novel antisense RNA, termed asRelE2, that co-regulates RelE2 production via targeted processing by the Mtb RNase III, Rnc. We find that convergent expression of this coding-antisense hybrid TA locus, relBE2-asrelE2, is controlled in a cAMP-dependent manner by the essential cAMP receptor protein transcription factor, Crp, in response to the host-associated stresses of low pH and nutrient limitation. Ex vivo survival studies with relE2 and asrelE2 knockout strains showed that RelE2 contributes to Mtb survival in activated macrophages and low pH to nutrient limitation. To our knowledge, this is the first report of a novel tripartite type IIb TA loci and antisense post-transcriptional regulation of a type II TA loci.

中文翻译：

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在结核分枝杆菌中发现一种新型 IIb RelBE 毒素-抗毒素系统，通过与反义 RNA 共同调节来定义

毒素-抗毒素基因座调节对与宿主环境和药物暴露相关的压力的适应性反应。系统基因组学研究表明，结核分枝杆菌编码一个自然扩展的 II 型毒素-抗毒素系统，包括 ParDE/RelBE 超家族成员。II 型毒素可能仅通过与 II 型抗毒素的蛋白质-蛋白质相互作用进行调节。然而，结核分枝杆菌的实验观察表明，在宿主相关的应激条件下，额外的控制机制调节 RelBE2 II 型基因座。在此，我们首次描述了一种称为 RelE2 的新型反义 RNA，它通过Mtb的靶向加工共同调节 RelE2 的产生RNase III，RNC。我们发现这种编码-反义杂合 TA 基因座relBE2-asrelE2的收敛表达由必需的 cAMP 受体蛋白转录因子 Crp 以 cAMP 依赖性方式控制，以响应宿主相关的低 pH 值和营养压力。局限性。对relE2和asrelE2敲除菌株的离体存活研究表明，RelE2 有助于Mtb在活化的巨噬细胞中的存活和低 pH 值对营养限制的影响。据我们所知，这是第一次报道新型三方 IIb 型 TA 基因座和 II 型 TA 基因座的反义转录后调控。