Center of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610093, China.
Central Laboratory, Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu 610081, China.
Nucleic Acids Res. 2022 Oct 14;50(18):10586-10600. doi: 10.1093/nar/gkac867.
Type II toxin-antitoxin (TA) systems are widely distributed in bacterial and archaeal genomes and are involved in diverse critical cellular functions such as defense against phages, biofilm formation, persistence, and virulence. GCN5-related N-acetyltransferase (GNAT) toxin, with an acetyltransferase activity-dependent mechanism of translation inhibition, represents a relatively new and expanding family of type II TA toxins. We here describe a group of GNAT-Xre TA modules widely distributed among Pseudomonas species. We investigated PacTA (one of its members encoded by PA3270/PA3269) from Pseudomonas aeruginosa and demonstrated that the PacT toxin positively regulates iron acquisition in P. aeruginosa. Notably, other than arresting translation through acetylating aminoacyl-tRNAs, PacT can directly bind to Fur, a key ferric uptake regulator, to attenuate its DNA-binding affinity and thus permit the expression of downstream iron-acquisition-related genes. We further showed that the expression of the pacTA locus is upregulated in response to iron starvation and the absence of PacT causes biofilm formation defect, thereby attenuating pathogenesis. Overall, these findings reveal a novel regulatory mechanism of GNAT toxin that controls iron-uptake-related genes and contributes to bacterial virulence.
II 型毒素-抗毒素（TA）系统广泛分布于细菌和古菌基因组中，参与多种关键的细胞功能，如防御噬菌体、生物膜形成、持久性和毒力。具有乙酰转移酶活性依赖性翻译抑制机制的 GCN5 相关 N-乙酰转移酶（GNAT）毒素代表了一个相对较新且不断扩大的 II 型 TA 毒素家族。我们在这里描述了一组广泛分布于假单胞菌属物种中的 GNAT-Xre TA 模块。我们研究了铜绿假单胞菌中的 PacTA（由 PA3270/PA3269 编码的成员之一），并证明 PacT 毒素正向调节铜绿假单胞菌中的铁摄取。值得注意的是，PacT 除了通过乙酰化氨酰-tRNA 来阻止翻译外，还可以直接结合 Fur（一种关键的铁摄取调节剂），降低其 DNA 结合亲和力，从而允许下游铁摄取相关基因的表达。我们进一步表明，pacTA 基因座的表达在铁饥饿和缺乏 PacT 时上调，导致生物膜形成缺陷，从而减弱了致病性。总的来说，这些发现揭示了一种新的 GNAT 毒素调控机制，该机制控制与铁摄取相关的基因，并有助于细菌的毒力。
