Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
Center for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka, India.
PLoS Pathog. 2022 Jun 3;18(6):e1010095. doi: 10.1371/journal.ppat.1010095. eCollection 2022 Jun.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), triggers enhanced accumulation of lipids to generate foamy macrophages (FMs). This process has been often attributed to the surge in the expression of lipid influx genes with a concomitant decrease in those involved in lipid efflux. Here, we define an Mtb-orchestrated modulation of the ubiquitination of lipid accumulation markers to enhance lipid accretion during infection. We find that Mtb infection represses the expression of the E3 ubiquitin ligase, ITCH, resulting in the sustenance of key lipid accrual molecules viz. ADRP and CD36, that are otherwise targeted by ITCH for proteasomal degradation. In line, overexpressing ITCH in Mtb-infected cells was found to suppress Mtb-induced lipid accumulation. Molecular analyses including loss-of-function and ChIP assays demonstrated a role for the concerted action of the transcription factor YY1 and the arginine methyl transferase PRMT5 in restricting the expression of Itch gene by conferring repressive symmetrical H4R3me2 marks on its promoter. Consequently, siRNA-mediated depletion of YY1 or PRMT5 rescued ITCH expression, thereby compromising the levels of Mtb-induced ADRP and CD36 and limiting FM formation during infection. Accumulation of lipids within the host has been implicated as a pro-mycobacterial process that aids in pathogen persistence and dormancy. In line, we found that perturbation of PRMT5 enzyme activity resulted in compromised lipid levels and reduced mycobacterial survival in mouse peritoneal macrophages (ex vivo) and in a therapeutic mouse model of TB infection (in vivo). These findings provide new insights into the role of PRMT5 and YY1 in augmenting mycobacterial pathogenesis. Thus, we posit that our observations could help design novel adjunct therapies and combinatorial drug regimen for effective anti-TB strategies.
结核分枝杆菌（Mtb）是结核病（TB）的病原体，它引发脂质的积累，从而产生泡沫巨噬细胞（FMs）。这一过程通常归因于脂质流入基因表达的激增，同时伴随着脂质流出相关基因的减少。在这里，我们定义了一种由 Mtb 协调的脂滴积累标记物的泛素化调节，以增强感染过程中的脂质积累。我们发现 Mtb 感染抑制了 E3 泛素连接酶 ITCH 的表达，导致关键脂质积累分子 ADRP 和 CD36 的持续存在，否则这些分子会被 ITCH 靶向进行蛋白酶体降解。同样，在 Mtb 感染的细胞中过表达 ITCH 被发现可以抑制 Mtb 诱导的脂质积累。包括功能丧失和 ChIP 测定在内的分子分析表明，转录因子 YY1 和精氨酸甲基转移酶 PRMT5 的协同作用在限制 Itch 基因的表达中起作用，通过在其启动子上赋予抑制性对称 H4R3me2 标记来实现。因此，siRNA 介导的 YY1 或 PRMT5 耗竭恢复了 ITCH 的表达，从而降低了 Mtb 诱导的 ADRP 和 CD36 水平，并限制了感染期间 FM 的形成。宿主内脂质的积累被认为是一种有利于病原体持续存在和休眠的促分枝杆菌过程。同样，我们发现 PRMT5 酶活性的扰动导致脂质水平降低和小鼠腹腔巨噬细胞（离体）和 TB 感染治疗性小鼠模型（体内）中分枝杆菌存活减少。这些发现为 PRMT5 和 YY1 在增强分枝杆菌发病机制中的作用提供了新的见解。因此，我们假设我们的观察结果可以帮助设计新的辅助治疗和联合药物方案，以实现有效的抗结核策略。
