Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
Department of Immunology, Duke University Medical Center, Durham, NC, USA.
FEBS J. 2021 Oct;288(20):5826-5849. doi: 10.1111/febs.15662. Epub 2021 Jan 12.
Disease-causing microorganisms not only breach anatomical barriers and invade tissues but also frequently enter host cells, nutrient-enriched environments amenable to support parasitic microbial growth. Protection from many infectious diseases is therefore reliant on the ability of individual host cells to combat intracellular infections through the execution of cell-autonomous defense programs. Central players in human cell-autonomous immunity are members of the family of dynamin-related guanylate binding proteins (GBPs). The importance of these interferon-inducible GTPases in host defense to viral, bacterial, and protozoan pathogens has been established for some time; only recently, cell biological and biochemical studies that largely focused on the prenylated paralogs GBP1, GBP2, and GBP5 have provided us with robust molecular frameworks for GBP-mediated immunity. Specifically, the recent characterization of GBP1 as a bona fide pattern recognition receptor for bacterial lipopolysaccharide (LPS) disrupting the integrity of bacterial outer membranes through LPS aggregation, the discovery of a link between hydrolysis-induced GMP production by GBP1 and inflammasome activation, and the classification of GBP2 and GBP5 as inhibitors of viral envelope glycoprotein processing via suppression of the host endoprotease furin have paved the way for a vastly improved conceptual understanding of the molecular mechanisms by which GBP nanomachines execute cell-autonomous immunity. The herein discussed models incorporate our current knowledge of the antimicrobial, proinflammatory, and biochemical properties of human GBPs and thereby provide testable hypotheses that will guide future studies into the intricacies of GBP-controlled host defense and their role in human disease.
致病微生物不仅突破解剖屏障并侵入组织，还经常进入富含营养的宿主细胞环境，有利于支持寄生微生物的生长。因此，许多传染病的预防依赖于单个宿主细胞通过执行细胞自主防御程序来对抗细胞内感染的能力。在人类细胞自主免疫中，动力蛋白相关鸟苷酸结合蛋白（GBP）家族成员是核心参与者。这些干扰素诱导的 GTP 酶在宿主防御病毒、细菌和原生动物病原体方面的重要性已经确立了一段时间；直到最近，主要集中在被酰化的同源物 GBP1、GBP2 和 GBP5 上的细胞生物学和生物化学研究为 GBP 介导的免疫提供了强大的分子框架。具体来说，最近将 GBP1 鉴定为细菌脂多糖（LPS）的真正模式识别受体，通过 LPS 聚集破坏细菌外膜的完整性，发现 GBP1 通过水解诱导 GMP 产生与炎症小体激活之间的联系，以及将 GBP2 和 GBP5 分类为通过抑制宿主内切蛋白酶弗林抑制病毒包膜糖蛋白加工的抑制剂，为更好地理解 GBP 纳米机器执行细胞自主免疫的分子机制铺平了道路。本文讨论的模型纳入了我们对人类 GBP 的抗菌、促炎和生化特性的现有认识，从而提供了可测试的假设，这些假设将指导未来对 GBP 控制的宿主防御及其在人类疾病中的作用的复杂性的研究。
