USP8 通过增强 ESCRT 介导的膜修复、限制增生和降低氧化应激,促进细胞内感染。

Pallavi Chandra, Jennifer A Philips
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引用次数: 0

摘要

宿主的 ESCRT 机器会修复受损的内溶酶体膜。如果损伤持续存在,则选择性大自噬/自噬会清除受损区室。结核分枝杆菌(Mtb)是一种细胞内病原体,它会破坏吞噬体膜,并将 ESCRT 介导的修复作为其毒力程序的目标。E3 泛素连接酶 PRKN 和 SMURF1 可促进自噬捕获受损的、含有 Mtb 的吞噬体。由于泛素化是一个可逆的过程,我们预计宿主的去泛素化酶(DUBs)也会参与其中。在这里,我们筛选了所有预测的小鼠 DUBs,以确定它们在泛素靶向和控制细胞内 Mtb 中的作用。我们发现 USP8(泛素特异性肽酶 8)与细胞内的 Mtb 共同定位,能识别吞噬体膜损伤,并且是依赖 ESCRT 的膜修复所必需的。此外,我们还发现 USP8 可调节 NFE2L2/NRF2 依赖性抗氧化特征。总之,我们的研究证明了 USP8 在通过促进吞噬体膜修复、限制泛素驱动的选择性自噬和减少氧化应激来促进 Mtb 细胞内生长方面的核心作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
USP8 promotes intracellular infection by enhancing ESCRT-mediated membrane repair, limiting xenophagy, and reducing oxidative stress.

The host ESCRT-machinery repairs damaged endolysosomal membranes. If damage persists, selective macroautophagy/autophagy clears the damaged compartment. Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that damages the phagosomal membrane and targets ESCRT-mediated repair as part of its virulence program. The E3 ubiquitin ligases PRKN and SMURF1 promote autophagic capture of damaged, Mtb-containing phagosomes. Because ubiquitination is a reversible process, we anticipated that host deubiquitinases (DUBs) would also be involved. Here, we screened all predicted mouse DUBs for their role in ubiquitin targeting and control of intracellular Mtb. We show that USP8 (ubiquitin specific peptidase 8) colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, we show that USP8 regulates the NFE2L2/NRF2-dependent antioxidant signature. Taken together, our study demonstrates a central role of USP8 in promoting Mtb intracellular growth by promoting phagosomal membrane repair, limiting ubiquitin-driven selective autophagy, and reducing oxidative stress.Abbreviation: BMDMs: bone marrow-derived macrophages; CFUs: colony-forming units; DUB: deubiquitinase; ESCRT: endosomal sorting complexes required for transport; LLOMe: L-leucyl-L-leucine methyl ester; MFI: mean fluorescence intensity; MOI: multiplicity of infection; Mtb: Mycobacterium tuberculosis; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; PMA: phorbol 12-myristate 13-acetate; ROS: reactive oxygen species; USP8: ubiquitin specific peptidase 8.

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