Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London SW7 2AZ, UK.
Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
Cell Host Microbe. 2024 Jun 12;32(6):913-924.e7. doi: 10.1016/j.chom.2024.04.012.
Aspects of how Burkholderia escape the host's intrinsic immune response to replicate in the cell cytosol remain enigmatic. Here, we show that Burkholderia has evolved two mechanisms to block the activity of Ring finger protein 213 (RNF213)-mediated non-canonical ubiquitylation of bacterial lipopolysaccharide (LPS), thereby preventing the initiation of antibacterial autophagy. First, Burkholderia's polysaccharide capsule blocks RNF213 association with bacteria and second, the Burkholderia deubiquitylase (DUB), TssM, directly reverses the activity of RNF213 through a previously unrecognized esterase activity. Structural analysis provides insight into the molecular basis of TssM esterase activity, allowing it to be uncoupled from its isopeptidase function. Furthermore, a putative TssM homolog also displays esterase activity and removes ubiquitin from LPS, establishing this as a virulence mechanism. Of note, we also find that additional immune-evasion mechanisms exist, revealing that overcoming this arm of the host's immune response is critical to the pathogen.
伯克霍尔德氏菌如何逃避宿主固有免疫反应，在细胞胞质溶胶中复制的问题仍然扑朔迷离。在这里，我们表明，伯克霍尔德氏菌进化出了两种机制来阻断环指蛋白 213（RNF213）介导的细菌脂多糖（LPS）非典型泛素化的活性，从而阻止抗菌自噬的起始。首先，伯克霍尔德氏菌的多糖荚膜阻止了 RNF213 与细菌的结合；其次，伯克霍尔德氏菌去泛素化酶（DUB）TssM 通过以前未被识别的酯酶活性直接逆转 RNF213 的活性。结构分析为 TssM 酯酶活性的分子基础提供了深入了解，使其能够与其异肽酶功能分离。此外，一个假定的 TssM 同源物也显示出酯酶活性，并从 LPS 上去除泛素，这确立了这是一种毒力机制。值得注意的是，我们还发现了其他的免疫逃避机制，这表明克服宿主免疫反应的这一方面对病原体至关重要。
