ESAT-6号
联想(心理学)
化学
细胞生物学
肺结核
免疫学
生物
结核分枝杆菌
医学
心理学
病理
心理治疗师
作者
Timothy A. Bates,Mila Trank-Greene,Xammy Nguyenla,Aidan Anastas,Sintayehu K Gurmessa,Ilaria R Merutka,Shandee D Dixon,Anthony Shumate,Abigail R Groncki,Matthew AH Parson,Jessica R. Ingram,Eric Barklis,John E. Burke,Ujwal Shinde,Hidde L. Ploegh,Fikadu Tafesse
出处
期刊:eLife
[eLife Sciences Publications Ltd]
日期:2023-12-01
卷期号:12
被引量:3
摘要
Mycobacterium tuberculosis (Mtb) is known to survive within macrophages by compromising the integrity of the phagosomal compartment in which it resides. This activity primarily relies on the ESX-1 secretion system, predominantly involving the protein duo ESAT-6 and CFP-10. CFP-10 likely acts as a chaperone, while ESAT-6 likely disrupts phagosomal membrane stability via a largely unknown mechanism. we employ a series of biochemical analyses, protein modeling techniques, and a novel ESAT-6-specific nanobody to gain insight into the ESAT-6’s mode of action. First, we measure the binding kinetics of the tight 1:1 complex formed by ESAT-6 and CFP-10 at neutral pH. Subsequently, we demonstrate a rapid self-association of ESAT-6 into large complexes under acidic conditions, leading to the identification of a stable tetrameric ESAT-6 species. Using molecular dynamics simulations, we pinpoint the most probable interaction interface. Furthermore, we show that cytoplasmic expression of an anti-ESAT-6 nanobody blocks Mtb replication, thereby underlining the pivotal role of ESAT-6 in intracellular survival. Together, these data suggest that ESAT-6 acts by a pH-dependent mechanism to establish two-way communication between the cytoplasm and the Mtb-containing phagosome.
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