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The merger that made us.
BMC Biology ( IF 5.4 ) Pub Date : 2020-06-24 , DOI: 10.1186/s12915-020-00806-3
Buzz Baum ₁ , David A Baum ₂

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Darwin was the first to imagine a tree of life with all living organisms at its branch tips, connected back through time to a single common ancestor at the base of the trunk. We now know that all known cellular life descended from a single rootstock, with bacteria and archaea, structurally simple prokaryotic cells that lack internal membrane-bound structures, making up the trees’ two main branches (see Fig. 1). Where on this tree, though, should we place animals and all the other organisms whose complex cells possess a nucleus and a labyrinthine endomembrane system, namely the eukaryotes? Phylogenetic analyses of eukaryotic genes have firmly established that eukaryotes first arose as the result of a merger of cells from two divergent, prokaryotic lineages [1, 2]. One of these two cells appears to have been a member of a subgroup of archaea, the so-called TACK archaea, which includes the widely studied Sulfolobus, whereas the other partner appears related to alpha-proteobacteria. Thus, the origin of eukaryotes is best depicted as a point of fusion on the tree of life (see large arrow on Fig. 1). Alpha-proteobacteria closely resemble mitochondria in many aspects of their structure and biochemistry, so these cells are thought to be the progenitors of mitochondria, leaving TACK as the presumed source of other components of the eukaryotic cell.

This raises a profound problem. How did two structurally simple prokaryotic cells come together to give rise to a complex eukaryotic cell? Historically, cell biological models assumed that the nucleus and endoplasmic reticulum evolved from the outside-in when invaginations of the plasma membrane of the archaeal host generated internal compartments via processes akin to endocytosis or phagocytosis. In 2014, however, we proposed an alternative “inside-out” model [3]. This flipped things around by envisioning the cytoplasm and endomembrane system gradually emerging from the elaboration of outward facing protrusions (see Fig. 2). Further, we speculated that the increase in the complexity of these protrusions over evolutionary time reflected a growing intimacy and increased metabolic exchange between the archaeal host and the once free-living proto-mitochondria. Whereas outside-in models assume that the plasma membrane remained in place during the evolution of eukaryotes, with the nuclear compartment arising from the coalescence of internalized membranes, the inside-out model posits that the inner nuclear membrane marks the boundary of the original archaeal host, with the endomembrane system and plasma membrane forming later as a result of the fusion of extracellular protrusions (see Fig. 2).

While one can imagine testing predictions of these alternative structural models of eukaryogenesis by studying the cell biology of present-day archaea, the large gulf that separates known TACK archaea and eukaryotes makes this difficult. With some interesting exceptions, TACK archaea have a standard prokaryotic organization with a membrane that consists of ether-linked, branched-chain lipids encased in a semi-crystalline glyco-protein coat. Progress has also been impeded by the fact that TACK archaeal cells tend to be small and to grow in environments we eukaryotes consider extreme—making them difficult to culture and study. Despite these challenges, work by several teams over a number of years has revealed a surprising number of cell biological features that TACK archaea share with eukaryotes. Like eukaryotes, TACK archaea have an ordered cell cycle, in which discrete phases of DNA replication and division are separated by gap phases [4]. In addition, many TACK archaea possess homologues of ESCRTIII proteins, which, like their eukaryotic counterparts, control cell division [5, 6], and also actin homologues that may help to shape these cells. Furthermore, TACK archaea share with eukaryotes a common pathway of N-linked glycosylation coupled transport of proteins across membranes, and they release membrane vesicles (including viral particles) generated via ESCRTIII-mediated scission [7], just as eukaryotes do. These latter facts imply that vesicle-based secretion in eukaryotes (including, multi-vesicular body formation) is based on pre-existing archaeal machinery. Nevertheless, many other proteins that play central roles in generating the dynamic and complex internal organization of a eukaryotic cell appear missing from the genomes of TACK archaea, including homologues of Dynamin, other ESCRT proteins, small regulatory GTPases and outer vesicle coat proteins, which play important roles in vesicle trafficking, and nuclear pore proteins. Without knowing the evolutionary origins of such proteins, it is difficult to reconstruct how cell structure acquired the levels of complexity seen in living eukaryotes.

Although a wide chasm remains, the gap between the prokaryotic and eukaryotic worlds closed significantly in 2015 when DNA isolated from environmental samples taken from the seabed off the coast of Norway was sequenced and organized into genomic assemblies [8]. This metagenomic work identified a “missing link”—a new record-holder for the closest living relative of eukaryotes. The Ettema group named this new microbe Lokiarchaeum and placed it close to the TACK clade as a new archaeal phylum, Lokiarchaeota. The genome of Loki, as it has come to be known, was found to contain a number of “eukaryotic signature proteins” not previously found in any prokaryote. This included homologues of the ubiquitin-ESCRT system, which controls membrane protein degradation and exosome formation in eukaryotes, and GTPases, including Rag-like GTPases, which in eukaryotes function at the lysosome. The genome also included actin homologues and, importantly, a small set of conserved eukaryotic-like actin regulators not found in TACK archaea. Strikingly, this was the case even though these organisms appear to possess classic archaeal lipids that are very different from those found in bacteria and eukaryotes. Since then, many new relatives of Lokiarchaeota have been identified, defining a new “Asgard” superphylum, some of whom may be even closer relatives of eukaryotes than Loki [2]. In the absence of live cultures, however, the morphology and behavior of Loki and other Asgards remained a matter of debate.

In 2020, a heroic 12-year effort by Imachi et al. to grow anaerobes from the bottom of the sea off the coast of Japan led to the fortuitous isolation of Prometheoarchaeum syntrophicum, another member of the Lokiarchaeota [9]. Although the team had hoped to generate pure cultures, this archaeon proved to be an obligate symbiont. Using electron microscopy, the team were able to obtain images of P. syntrophicum cells in mixed cultures. Strikingly, in these electronmicrographs many P. syntrophicum cells appeared similar to an early intermediate in the path to eukaryogenesis imagined in the inside-out model. Cells lacked internal membrane-bound compartments but, instead, possessed a central “nuclear-like” cell body, as well as external blebs and long finger-like protrusions. Further, in line with the inside-out hypothesis, Imachi et al. suggested that these extracellular protrusions may facilitate the exchange of material with their obligate extracellular symbionts.

The characterization of the first species of Lokiarchaeota has helped make the case that much of the machinery required to generate eukaryotic cellular complexity was already present in archaeal ancestors prior to the acquisition of mitochondria. However, it is clear that there are also many features of eukaryotic cell biology that are missing from Asgard archaea, including bacterial-type lipids, which are likely to be important for dynamic membrane fission-fusion reactions. Furthermore, there is no evidence of archaea undergoing a process akin to endocytosis, which frequently relies on the activity of Dynamin, a protein that eukaryotes appear to have acquired from the mitochondrial symbiont [10]. Thus, it seems clear that full-blown eukaryotic vesicle trafficking arose only after the archaeal eukaryotic ancestor established a close and stable association with a bacterial partner from which it acquired lipids and other, mainly metabolic, genes (see fusion point in Fig. 1). These bacterial novelties enabled proto-eukaryotic cells to elaborate on their basic cellular body plan—a likely pre-requisite for their subsequent radiation into important new ecological niches, from amoeboid-like predation to multicellularity.

The recent discovery of Loki and other Asgard archaea has ignited research into eukaryotic origins. At the same time, advances in metagenomics, phylogenetics, and archaeal molecular biology have put in place many of the tools required to test predictions of different models of eukaryogenesis. Next steps will surely involve an exploration of the cellular and ecological diversity of Asgards and their symbiotic partners, as well as in-depth study of the structure and activities of archaeal homologues of key eukaryotic proteins in vitro, and their potential functions in a few experimentally tractable model systems, like Sulfolobus. The success in culturing P. syntrophicum from environmental samples also makes clear how much there is yet to learn about microbial diversity in nature. Indeed, there is a real chance of identifying other intermediates in stable partnerships with proteobacteria that might represent sister groups that are even closer to eukaryotes than Lokiarchaeota (depicted by a “?” in Fig. 1). Thus, while we now know so much more about the origin of eukaryotes than we did in 2014, fleshing out the details remains a thrilling prospect for the years ahead.

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We thank Jake Baum, Gautam Dey, Manu Hegde, Martin Raff, and Tom Williams for comments on the text and Josh Baum, Sam Baum, and Sarah Friedrich for help with the figures..

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The authors declare that they have no competing interests.

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MRC-Laboratory of Molecular Cell Biology and the Institute for the Physics of Living Systems, UCL, Gower Street, London, WC1E6BT, UK
Buzz Baum
University of Wisconsin – Madison, 430 Lincoln Drive, Madison, WI, 53726, USA
David A. Baum

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Baum, B., Baum, D.A. The merger that made us. BMC Biol 18, 72 (2020). https://doi.org/10.1186/s12915-020-00806-3

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Published: 24 June 2020
DOI: https://doi.org/10.1186/s12915-020-00806-3

中文翻译：

合并使我们成为现实。

达尔文是第一个想到生命树的人，它的所有生物都在其分支的顶端，随着时间的流逝，它与树干底部的单个共同祖先相连。现在我们知道，所有已知的细胞生命都来自单一的砧木，细菌和古细菌是结构简单的原核细胞，缺乏内部的膜结合结构，构成了树木的两个主要分支（见图1）。但是，我们应该在这棵树上的什么地方放置动物以及所有其他具有复杂细胞核和迷宫式内膜系统的生物，即真核生物？真核生物基因的系统发育分析已牢固地确定，真核生物首先是来自两个不同的原核世系的细胞合并的结果[1，2]。这两个单元格之一似乎是古细菌亚组的成员，Sulfolobus，而另一个伴侣似乎与α-变形杆菌有关。因此，真核生物的起源最好被描述为生命树上的一个融合点（见图1中的大箭头）。α-蛋白细菌在其结构和生化的许多方面都非常类似于线粒体，因此这些细胞被认为是线粒体的祖细胞，而TACK被认为是真核细胞其他成分的来源。

这就提出了一个深刻的问题。两个结构简单的原核细胞如何聚集在一起形成复杂的真核细胞？从历史上看，细胞生物学模型假设当古细菌宿主质膜的入侵通过类似于内吞作用或吞噬作用的过程产生内部区室时，核和内质网从外而内演化。然而，在2014年，我们提出了另一种“由内而外”的模型[3]。通过设想从向外突出的突起逐渐出现的细胞质和内膜系统，这可以扭转局面（见图2）。进一步，我们推测，随着进化时间的推移，这些突起的复杂性的增加反映了古细菌宿主和曾经自由生活的线粒体之间亲密关系的增加和新陈代谢的交换。外而内的模型认为质膜在真核生物的进化过程中仍保留在原位，而核室是由内在的膜结合而形成的，而内而外的模型则认为内核膜是原始古细菌宿主的边界。，由于细胞外突起的融合，膜内系统和质膜随后形成（参见图2）。

尽管可以通过研究当今古细菌的细胞生物学来想象对真核生物这些替代结构模型的预测预测，但是将已知的TACK古细菌和真核生物分开的巨大鸿沟使这一工作变得困难。除了一些有趣的例外，TACK古细菌具有一个标准的原核组织，其膜由包裹在半结晶糖蛋白涂层中的醚连接的支链脂质组成。TACK古细菌细胞往往很小并且会在我们真核生物认为极端的环境中生长，这使它们难以培养和研究，这也阻碍了进展。尽管存在这些挑战，但数支团队多年来的工作揭示了TACK古细菌与真核生物共有的惊人数量的细胞生物学特征。像真核生物一样 TACK古细菌具有一个有序的细胞周期，其中DNA复制和分裂的离散相被间隔相隔开[4]。另外，许多TACK古细菌拥有ESCRTIII蛋白的同源物，就像它们的真核对应物一样，它们控制细胞分裂[5，6]，还有可能有助于塑造这些细胞的肌动蛋白同源物。此外，TACK古细菌与真核生物共享蛋白质跨膜的N联糖基化偶联转运的共同途径，就像真核生物一样，它们释放通过ESCRTIII介导的分裂产生的膜囊泡（包括病毒颗粒）[7]。这些后面的事实暗示真核生物中基于囊泡的分泌（包括多囊体形成）基于先前存在的古细菌机器。不过，TACK古细菌的基因组中缺少许多其他在产生真核细胞的动态和复杂内部组织中起关键作用的蛋白质，包括Dynamin的同系物，其他ESCRT蛋白，小的调节性GTPases和外部囊泡外壳蛋白，这些蛋白起着重要的作用在囊泡运输和核孔蛋白中。在不了解此类蛋白质的进化起源的情况下，很难重建细胞结构如何获得在真核生物中看到的复杂性水平。

尽管仍然存在巨大的鸿沟，但2015年，当从挪威沿海海底环境样本中分离的DNA进行测序并组织成基因组时，原核和真核世界之间的鸿沟大大缩小了[8]。这项宏基因组学研究确定了“缺失的环节”，即真核生物最亲近的亲属的新记录保持者。Ettema小组将这种新微生物命名为Lokiarchaeum并将其放置在TACK进化枝附近，作为新的古细菌门Lokiarchaeota。众所周知，Loki的基因组包含许多以前在任何原核生物中都找不到的“真核签名蛋白”。这包括控制真核生物中膜蛋白降解和外泌体形成的泛素-ESCRT系统的同源物，以及包括真核生物在溶酶体中起作用的Rag样GTPases在内的GTPases。基因组还包括肌动蛋白同源物，重要的是，还有一小部分在TACK古细菌中找不到的保守的真核样肌动蛋白调节剂。令人惊讶的是，即使这些生物似乎拥有与细菌和真核生物中所发现的经典古细菌脂质非常不同的情况，也是如此。从那时起，已经确定了Lokiarchaeota的许多新亲戚，。然而，在没有活文化的情况下，Loki和其他Asgards的形态和行为仍然是一个争论的问题。

2020年，Imachi等人做出了12年的英勇努力。在日本沿海从海底生长厌氧菌导致了Prokieoarchaeum syntrophicum（Lokiarchaeota的另一个成员）的偶然隔离[9]。尽管该团队曾希望产生纯净的文化，但这种古细菌被证明是专一的共生体。使用电子显微镜，研究小组能够获得混合培养中的食肉毕赤酵母细胞的图像。引人注目的是，在这些电子显微照片中，许多对虾细胞的出现类似于由内而外的模型所想象的真核生成途径中的早期中间体。细胞没有内部膜结合区室，而是拥有中央的“核样”细胞体，以及外部气泡和长手指状突起。此外，根据从内而外的假设，Imachi等人。提示这些细胞外突起可能有助于与其专心的细胞外共生体交换物质。

Lokiarchaeota的第一个物种的特征已帮助证明，线粒体收购之前，古细菌祖先已经存在产生真核细胞复杂性所需的许多机制。然而，很明显，阿斯加德古细菌还缺少真核细胞生物学的许多特征，包括细菌型脂质，这对于动态膜裂变融合反应可能很重要。此外，没有证据表明古细菌经历类似于内吞作用的过程，该过程通常依赖于动力蛋白的活性，该蛋白是真核生物似乎从线粒体共生体中获得的一种蛋白质[10]。从而，似乎很清楚，只有在真核祖先祖先与细菌伙伴建立了紧密而稳定的联系之后，才开始出现成熟的真核小囊贩运，细菌伴侣从中获得了脂质和其他主要是代谢基因（见图1的融合点）。这些细菌的新颖性使原真核细胞能够阐明其基本的细胞身体计划，这可能是其随后辐射入重要的新生态位的先决条件，这些新生态位从类阿米巴类动物掠食到多细胞性。

Loki和其他Asgard古细菌的最新发现激发了对真核生物起源的研究。同时，宏基因组学，系统发育学和古细菌分子生物学方面的进展已经提供了许多工具，可用于测试对不同真核发生模型的预测。下一步肯定会涉及对Asgards及其共生伙伴的细胞和生态多样性的探索，以及对关键真核蛋白质的古细菌同源物的结构和活性的深入研究，以及它们在一些实验中的潜在功能。易处理的模型系统，例如Sulfolobus。培养食肉单胞菌的成功从环境样本中也可以清楚地了解自然界中微生物多样性的知识。确实，确实存在与蛋白菌稳定伴侣关系中鉴定其他中间物的机会，这些中间物可能代表的姐妹群体比真核生物更接近真核生物（在图1中用“？”表示）。因此，虽然我们现在对真核生物的了解比2014年要多得多，但充实细节仍然是未来几年令人振奋的前景。

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感谢Jake Baum，Gautam Dey，Manu Hegde，Martin Raff和Tom Williams对文本的评论，以及Josh Baum，Sam Baum和Sarah Friedrich对这些数字的帮助。

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Buzz Baum
威斯康星大学麦迪逊分校，林肯大道430号，麦迪逊，威斯康星州53726
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对应于Buzz Baum或David A. Baum。

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