The study, published Feb. 8 in the journal Nature, also sheds light on how that shared, ancient machinery — a cluster of enzymes known as ubiquitin transferases — works.

这项研究发表在2月8日的《自然》杂志上，阐明了这种共享的古老机制——一组被称为泛素转移酶的酶——是如何工作的。

Better understanding, and potentially reprogramming this machine, could ultimately pave the way to novel approaches for treating a host of human diseases, from autoimmune disorders like Rheumatoid arthritis and Crohn’s disease to neurodegenerative diseases like Parkinson’s disease, the authors said.

作者说，更好地了解并可能对这台机器进行重新编程，最终可能为治疗一系列人类疾病铺平道路，从类风湿关节炎和克罗恩病等自身免疫性疾病到帕金森病等神经退行性疾病。

“This study demonstrates that we’re not all that different from bacteria,” said senior author Aaron Whiteley, an assistant professor in the Department of Biochemistry. “We can learn a lot about how the human body works by studying these bacterial processes.”

该研究的资深作者、生物化学系助理教授亚伦·怀特利说:“这项研究表明，我们与细菌并没有那么大的不同。”“通过研究这些细菌过程，我们可以了解很多关于人体如何工作的信息。”

The next CRISPR?

下一个CRISPR?

The study is not the first to showcase the lessons bacteria can teach humans.

这并不是第一个展示细菌可以教给人类什么的研究。

Mounting evidence suggests that portions of the human immune system may have originated in bacteria, with evolution yielding more complex iterations of bacterial virus-fighting tools across plant and animal kingdoms.

越来越多的证据表明，人类免疫系统的一部分可能起源于细菌，随着进化，在植物和动物王国中产生了更复杂的细菌病毒对抗工具。

In 2020, University of California Berkeley biochemist Jennifer Doudna won the Nobel Prize for CRISPR, a gene-editing tool that repurposes another obscure system bacteria use to fight off their own viruses, known as phages.

2020年，加州大学伯克利分校的生物化学家詹妮弗·杜德纳(Jennifer Doudna)因CRISPR获得了诺贝尔奖，CRISPR是一种基因编辑工具，它重新利用了细菌用来对抗自身病毒的另一种鲜为人知的系统，即噬菌体。

The buzz around CRISPR ignited renewed scientific interest in the role proteins and enzymes play in anti-phage immune response.

围绕CRISPR的热议重新点燃了科学家对蛋白质和酶在抗噬菌体免疫反应中所起作用的兴趣。

“Over the past three to five years people have realized it doesn’t end with CRISPR. The potential is so much bigger,” said Whiteley.

“在过去的三到五年里，人们已经意识到它不会随着CRISPR而结束。潜力要大得多，”怀特利说。

Missing link in evolutionary history

进化史上缺失的一环

For the study, Whiteley and co-first author Hannah Ledvina, a Jane Coffin Childs Postdoctoral Fellow in the department, collaborated with University of California San Diego biochemists to learn more about a protein called cGAS (cyclic GMP-AMP synthase), previously shown to be present in both humans and, in a simpler form, bacteria.

在这项研究中，Whiteley和共同第一作者Hannah Ledvina (Jane Coffin Childs博士后)与加州大学圣地亚哥分校的生物化学家合作，更多地了解了一种名为cGAS(环gp – amp合成酶)的蛋白质，这种蛋白质以前被证明存在于人类和一种更简单的形式——细菌中。

In bacteria and in humans, cGAS is critical for mounting a downstream defense when the cell senses a viral invader. But what regulates this process in bacteria was previously unknown.

在细菌和人类中，当细胞感知到病毒入侵时，cGAS对于建立下游防御至关重要。但是，是什么在细菌中调控这一过程，以前是未知的。

Using an ultra-high-resolution technique called cryo-electron microscopy alongside other genetic and biochemical experiments, Whiteley’s team took an up-close look at the structure of cGAS’s evolutionary predecessor in bacteria and discovered additional proteins that bacteria use to help cGAS defend the cell from viral attack.

Whiteley的团队使用一种称为低温电子显微镜的超高分辨率技术以及其他遗传和生化实验，近距离观察了细菌中cGAS进化前身的结构，并发现了细菌用来帮助cGAS保护细胞免受病毒攻击的额外蛋白质。

Specifically, they discovered that bacteria modify their cGAS using a streamlined “all-in-one version” of ubiquitin transferase, a complex collection of enzymes that in humans control immune signaling and other critical cellular processes.

具体来说，他们发现细菌使用一种流线型的泛素转移酶来修饰它们的cGAS，泛素转移酶是一种复杂的酶集合，在人类中控制免疫信号和其他关键的细胞过程。

Because bacteria are easier to genetically manipulate and study than human cells, this discovery opens a new world of opportunity for research, said Ledvina.

Ledvina说，因为细菌比人类细胞更容易在基因上操纵和研究，这一发现为研究打开了一个新的机会世界。

“The ubiquitin transferases in bacteria are a missing link in our understanding of the evolutionary history of these proteins.”

“细菌中的泛素转移酶是我们对这些蛋白质进化史的理解中缺失的一环。”

Editing proteins

编辑蛋白质

The study also revealed just how this machine works, identifying two key components — proteins called Cap2 and Cap3 (CD-NTase-associated protein 2 and 3) — which serve, respectively, as on and off switches for the cGAS response.

这项研究还揭示了这台机器是如何工作的，确定了两个关键成分——叫做Cap2和Cap3 (cd – nase相关蛋白2和3)的蛋白质，它们分别充当cGAS反应的开关。

Whiteley explained that in addition to playing a key role in immune response, ubiquitin in humans can serve as a sort of marker for cellular garbage, directing excess or old proteins to be broken down and destroyed. When that system misfires due to mutations in the machine, proteins can build up and diseases, such as Parkinson’s, can occur.

Whiteley解释说，除了在免疫反应中发挥关键作用外，人体内的泛素还可以作为细胞垃圾的一种标记物，指导过量或旧的蛋白质被分解和破坏。当该系统因机器突变而失效时，蛋白质就会堆积，帕金森病等疾病就会发生。

The authors stress that far more research is needed but the discovery opens exciting scientific doors. Just as scientists adapted the ancient bacterial defense system CRISPR into scissor-like biotechnology that can snip mutations out of DNA, Whiteley believes pieces of the bacterial ubiquitin transferase machine — namely Cap3, the “off switch” — could ultimately be programmed to edit out problem proteins and treat disease in humans.

作者强调，还需要进行更多的研究，但这一发现打开了令人兴奋的科学之门。就像科学家们将古老的细菌防御系统CRISPR改造成剪刀状的生物技术，可以从DNA中剪切突变一样，Whiteley相信，细菌泛素转移酶机器的片段——即Cap3，即“关闭开关”——最终可以被编程来编辑出问题蛋白质并治疗人类疾病。

He and his team, with the help of Venture Partners at CU Boulder, have already filed for intellectual property protection, and they’re moving forward with more research.

他和他的团队在科罗拉多大学博尔德分校的Venture Partners的帮助下，已经申请了知识产权保护，他们正在进行更多的研究。

Read more at Sciencedaily.org

文章来自Sciencedaily.org

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