水木视界vol.2丨人类细胞用肥皂般的蛋白质抵御细菌入侵

转载自Smithsonian:

"Human Cells Ward Off Bacterial Invaders With a Protein That Behaves Like Soap"

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当细菌越过我们的免疫细胞时，身体还有一招。非免疫细胞加入战斗，释放出一种类似肥皂的蛋白质，对细菌入侵者的墙壁进行撕咬。

When bacteria get past our immune cells, the body has one more trick up its sleeve. The nonimmune cells join the fight by unleashing a soap-like protein that takes a bite out of the walls of the bacterial invaders.

"耶鲁大学的免疫学家John MacMicking告诉《Science News》的Jonathan Lambert说："我们对在人类细胞内发现类似洗涤剂的活动感到有点惊讶。"

“We were a bit surprised to find detergent-like activity inside human cells,” John MacMicking, an Yale University immunologist, tells Jonathan Lambert of Science News.

最近发表在《Science》杂志上的这项新研究，让我们看到了人体为抵御病原体渗透而采取的复杂策略。虽然免疫细胞和抗体占据了研究界的大部分注意力，但这项新研究将焦点转向了经常被忽视的非免疫细胞的细胞防御。这些细胞是 "一个古老而原始的防御系统 "的重要参与者，MacMicking告诉科学新闻。

The new study, recently published in the journal Science, provides a glimpse of the complex strategies that the human body employs to defend itself against pathogenic infiltrators. While immune cells and antibodies hog most of the attention from the research community, the new research turns the spotlight onto the oft-overlooked cellular defenses of nonimmune cells. These cells are important players of “an ancient and primordial defense system,” MacMicking tells Science News.

这种能杀死细菌的、类似肥皂的蛋白质是一种叫做APOL3的载脂蛋白。《Scientist》杂志的Abby Olena报道说，载脂蛋白通常用于在身体周围运送脂质分子，以作为能量或用于构建细胞。像肥皂一样，APOL3分子包含一个亲水端和一个亲脂肪端，因此它可以与细菌的脂质膜结合，并将大块的壁溶解到细胞内液中。此外，MacMicking的团队在整个身体的各种组织中发现了APOL3，因此研究人员怀疑它可以提供广泛的保护。

The bacteria-slaying, soap-like protein is an apolipoprotein called APOL3. Apolipoproteins are normally used for ferrying lipids molecules around the body to be used as energy or for building cells, reports Abby Olena for The Scientist. Like soap, the APOL3 molecules contains a water-loving end and a fat-loving end, so it can bind to the lipid membranes of bacteria and dissolve chunks of the wall into the intracellular fluid. Moreover, MacMicking’s team found APOL3 in a variety of tissues throughout the body, so the researchers suspect it could offer wide protection.

为了研究这种细胞防御机制，MacMicking和他的同事用沙门氏菌感染了人类上皮细胞，沙门氏菌是造成食物中毒的病菌。根据霍华德-休斯医学研究所的一份声明，该细菌拥有两层膜：外层膜用于装甲，内层膜则用于保护其免受抗生素等威胁。

To study this cellular defense mechanism, MacMicking and his colleagues infected human epithelial cells with Salmonella, the germ responsible for food-poisoning. The bacterium possesses two membranes: an outer one for armor and an inner one as protection against threats such as antibiotics, according to a Howard Hughes Medical Institute statement.

在筛选了超过19000个人类基因后，研究人员发现APOL3与GBP1蛋白协同工作，以击溃沙门氏菌。在高分辨率显微镜的帮助下，研究人员拼凑出了这对蛋白质是如何抵御细菌的。在收到来自免疫系统的红色警报信号后，非免疫细胞会大规模地产生这两种蛋白质。GBP1对沙门氏菌的外膜进行第一轮打击，让APOL3通过并打破内膜。杀手级的APOL3蛋白随后蜂拥而至，将细菌消灭。

After screening over 19,000 human genes, the researchers found that APOL3 works in concert with the GBP1 protein to wreck Salmonella. With the aid of a high-resolution microscope, the researchers pieced together how the proteinaceous pair defend against bacteria. Upon receiving red-alert signals from the immune system, non-immune cells churn out both proteins en masse. GBP1 lands the first blow on Salmonella’s outer membrane, allowing APOL3 to pass through and break apart the inner membrane. The killer APOL3 protein then swarms the bacteria and destroys them.

当沙门氏菌（红色）侵入细胞时，APOL3（绿色）粘附在细菌的表面并将其分解。(GIF加载较慢)

When Salmonella (red) invades a cell, APOL3 (green) gloms on to the bacterium’s surface and breaks it apart. 

@R. Gaudet et al. / Science 2021

在杀死沙门氏菌之前，类似洗涤剂的蛋白质APOL3（绿色）必须穿过细菌的保护性外膜（红色）

Before killing Salmonella, the detergent-like protein APOL3 (green) must get through the bacteria's protective outer membrane (red). 

@R. Gaudet et al. / Science 2021

研究人员还发现APOL3以细菌膜中的脂质为目标，而放过了自己的宿主。这种狡猾的蛋白质通过避开胆固醇来区分这两种物质，而胆固醇经常在哺乳动物细胞壁中发现。

The researchers also found APOL3 targets the lipids in bacterial membranes and spares its own host. The wily protein distinguishes the two kinds by avoiding cholesterol, which is often found in the walls of mammalian cells.

"伊利诺伊大学厄巴纳-香槟分校的进化免疫学家Jessica Brinkworth告诉《Science News》说："关于这些发现的一切都是超级酷的。她称APOL3对其细菌目标的选择性是 "一件美丽的事情"。

“Everything about these findings is supercool,” evolutionary immunologist Jessica Brinkworth of the University of Illinois at Urbana-Champaign who wasn’t involved in the study, tells Science News. She calls APOL3’s selectivity of its bacterial targets “a beautiful thing.”

MacMicking说他的下一步行动是揭开与APOL3相关的其他脂蛋白的潜在防御策略。根据声明，他还希望该研究的发现能够指导未来开发细菌感染新疗法的努力。

MacMicking says his next move is to uncover the potential defense strategies of other apolipoproteins related to APOL3. He also hopes the study’s findings can guide future efforts to develop new treatments for bacterial infections, per the statement.

"这是一个人类自己制造抗生素的案例，其形式是一种像洗涤剂一样作用的蛋白质，"MacMicking在声明中说。"我们可以从中学习。"

“This is a case where humans make their own antibiotic in the form a protein that acts like a detergent,” says MacMicking in the statement. “We can learn from that.”

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相关Science文章:

"A human apolipoprotein L with detergent-like activity kills intracellular pathogens"

我们确定ISG apolipoprotein L3（APOL3）是一种能够杀死细胞膜侵入性细菌的强有力的效应蛋白。人类APOL家族是一个由六个基因组成的集群，在模拟灵长类动物的正向选择下迅速进化；然而，除了创始成员APOL1（一种分泌的细胞外蛋白，形成人类血清的锥虫因子）外，细胞内APOL家族成员的功能尚不清楚。经遗传工程改造为缺乏APOL3的人类细胞在IFN-γ激活后未能控制多种细胞膜侵袭性革兰氏阴性细菌的复制。这种发现在初级人类肠道上皮细胞、肠道肌成纤维细胞和静脉内皮细胞中得到了验证--所有的细胞目标通常不被视为免疫系统的一部分。

We identify the ISG apolipoprotein L3 (APOL3) as a potent effector protein capable of killing cytosol-invasive bacteria. The human APOL family is a cluster of six genes that have evolved rapidly under positive selection in simian primates; however, aside from the founding member APOL1, a secreted extracellular protein that forms the trypanolytic factor of human serum, the function of the intracellular APOL family members is unknown. Human cells genetically engineered to lack APOL3 failed to control the replication of multiple cytosol-invasive Gram-negative bacteria after IFN-γ activation. Such findings were validated in primary human intestinal epithelial cells, intestinal myofibroblasts, and venular endothelium—all cellular targets not typically considered part of the immune system. 

我们通过活体显微镜跟踪APOL3，发现它迅速转移到暴露在细胞膜上的细菌，而其他APOL家族成员则没有。超分辨率成像、生物工程报告器和无细胞重组的组合显示，当APOL3瞄准IFN-γ激活的细胞内的病原体时，它对细菌内膜（IM）造成了致命的伤害。在这里，APOL3与其他ISG编码的蛋白协同作用，包括鸟苷酸结合蛋白1（GBP1），扰乱细菌O型抗原外膜（OM）的通透性屏障，使APOL3能够进入IM下方。

Using a panel of compositionally distinct liposome targets, we found that APOL3 membranolytic activity toward microbial rather than host endomembranes stemmed from an ability to dissolve bacterial polyanionic lipid substrates lacking cholesterol into discoidal lipoprotein complexes; single-particle cryo–electron microscopy found that these complexes resembled apolipoprotein­ scaffold “nanodiscs.” Corroborating these findings in live bacteria by native mass spectrometry, we found that APOL3 transitioned from a partially disordered lipid-free state to tightly folded lipoprotein nanodiscs upon extracting lipid from the IM—a process that resulted in rapid death of the bacterium. 

利用一组成分不同的脂质体目标，我们发现APOL3对微生物而非宿主内膜的溶膜活性源于将缺乏胆固醇的细菌多离子脂质底物溶解为盘状脂蛋白复合物的能力；单粒子冷冻电镜发现这些复合物类似于脂蛋白支架 "纳米盘"。通过原生质谱法证实了这些发现，我们发现APOL3在从IM中提取脂质时，从部分无序的脂质状态过渡到紧密折叠的脂蛋白纳米盘，这一过程导致了细菌的快速死亡。

We tracked APOL3 by live microscopy and found that it rapidly relocated to cytosol-exposed bacteria, whereas other APOL family members did not. A combination of superresolution imaging, bioengineered reporters, and cell­ free reconstitution revealed that when APOL3 targets pathogens inside IFN-γ–activated cells, it inflicts a lethal insult to the bacterial inner membrane (IM). Here APOL3 synergizes with other ISG-encoded proteins, including guanylate-binding protein 1 (GBP1), that perturb the bacterial O­ antigen outer membrane (OM) permeability barrier to allow APOL3 access to the IM underneath. 

水木视界丨vol. 2

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