Acetylation of Cyclic AMP Receptor Protein by Acetyl Phosphate Modulates Mycobacterial Virulence.
Acetylation of Cyclic AMP Receptor Protein by Acetyl Phosphate Modulates Mycobacterial Virulence.
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DOI：
10.1128/spectrum.04002-22
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发表时间：
2023-02-14
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
结核分枝杆菌(Mtb)作为病原体的成功部分归因于它对动态宿主微环境的感知和响应能力。环磷酸腺苷(CAMP)受体蛋白(CRP)与结核分枝杆菌的致病性密切相关，并在此过程中发挥重要作用。然而，当Mtb对其环境做出反应时，指导CRP自身调节和下游靶基因的分子机制还不完全清楚。在这里，它证明了保守的赖氨酸193(K193)在C末端DNA结合域的乙酰化降低了它的DNA结合能力并抑制了转录活性。CRPK193的可逆乙酰化状态被证明显著影响分枝杆菌的生长表型，改变应激反应，并通过CRPK193位点特异性突变调节生物相关基因的表达。值得注意的是，在包括cAMP、低pH、高温和氧化应激在内的CRP激活条件下，K193的乙酰化水平降低，这表明微环境信号可以直接调节CRPK193的乙酰化。基于细胞和小鼠的感染分析都证实了CRPK193对结核分枝杆菌毒力的调节至关重要。此外，CRPK193的乙酰化依赖于细胞内的代谢中间产物乙酰磷酸(ACP)，而去乙酰化是由依赖NAD+的脱乙酰酶介导的。这些结果表明，ACP介导的CRPK193乙酰化降低了CRP的活性，并负面调节了结核分枝杆菌的致病性。我们认为，转录、翻译后修饰和代谢物之间的串扰机制是病原菌的常见调控机制。结核分枝杆菌(Mtb)是结核病的病原体，其在恶劣宿主条件下生存的能力一直是人们深入研究的主题。因此，我们探索了Mtb对环境做出反应时引导CRP下游靶基因的分子机制。我们的研究对文献有贡献，因为我们描述了乙酰化K193在调节其与靶DNA的结合亲和力和影响分枝杆菌毒力方面的作用。我们发现，分枝杆菌可以通过CRPK193的可逆乙酰化来调节其致病性，这种可逆乙酰化是由ACP和依赖NAD+的脱乙酰酶介导的。CRPMtb通过翻译后修饰、转录水平和代谢中间产物的调节有助于更好地理解它在分枝杆菌生存和致病中的作用。
The success of Mycobacterium tuberculosis (Mtb) as a pathogen is partly attributed to its ability to sense and respond to dynamic host microenvironments. The cyclic AMP (cAMP) receptor protein (CRP) is closely related to the pathogenicity of Mtb and plays an important role in this process. However, the molecular mechanisms guiding the autoregulation and downstream target genes of CRP while Mtb responds to its environment are not fully understood. Here, it is demonstrated that the acetylation of conserved lysine 193 (K193) within the C-terminal DNA-binding domain of CRP reduces its DNA-binding ability and inhibits transcriptional activity. The reversible acetylation status of CRP K193 was shown to significantly affect mycobacterial growth phenotype, alter the stress response, and regulate the expression of biologically relevant genes using a CRP K193 site-specific mutation. Notably, the acetylation level of K193 decreases under CRP-activating conditions, including the presence of cAMP, low pH, high temperature, and oxidative stress, suggesting that microenvironmental signals can directly regulate CRP K193 acetylation. Both cell- and murine-based infection assays confirmed that CRP K193 is critical to the regulation of Mtb virulence. Furthermore, the acetylation of CRP K193 was shown to be dependent on the intracellular metabolic intermediate acetyl phosphate (AcP), and deacetylation was mediated by NAD+-dependent deacetylases. These findings indicate that AcP-mediated acetylation of CRP K193 decreases CRP activity and negatively regulates the pathogenicity of Mtb. We believe that the underlying mechanisms of cross talk between transcription, posttranslational modifications, and metabolites are a common regulatory mechanism for pathogenic bacteria. IMPORTANCE Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, and the ability of Mtb to survive harsh host conditions has been the subject of intensive research. As a result, we explored the molecular mechanisms guiding downstream target genes of CRP when Mtb responds to its environment. Our study makes a contribution to the literature because we describe the role of acetylated K193 in regulating its binding affinity to target DNA and influencing the virulence of mycobacteria. We discovered that mycobacteria can regulate their pathogenicity through the reversible acetylation of CRP K193 and that this reversible acetylation is mediated by AcP and a NAD+-dependent deacetylase. The regulation of CRPMtb by posttranslational modifications, at the transcriptional level, and by metabolic intermediates contribute to a better understanding of its role in the survival and pathogenicity of mycobacteria.
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影响因子：
3.6
作者：
Liarzi, Orna;Barak, Rina;Eisenbach, Michael
通讯作者：
Eisenbach, Michael
影响因子：
2.8
作者：
Agarwal, Nisheeth;Raghunand, Tirumalai R.;Bishai, William R.
通讯作者：
Bishai, William R.
APRABC：结核分枝杆菌的复杂特异性基因座，可调节pH驱动的巨噬细胞吞噬体。
影响因子：
3.6
作者：
Abramovitch RB;Rohde KH;Hsu FF;Russell DG
通讯作者：
Russell DG
DOI：
10.1016/j.ijid.2022.03.011
发表时间：
2022-11
期刊：
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
影响因子：
--
作者：
Chakaya J;Petersen E;Nantanda R;Mungai BN;Migliori GB;Amanullah F;Lungu P;Ntoumi F;Kumarasamy N;Maeurer M;Zumla A
通讯作者：
Zumla A
影响因子：
3.2
作者：
Bai, GC;McCue, LA;McDonough, KA
通讯作者：
McDonough, KA