PNAS & PLoS Comput Biol：揭示链霉菌菌丝产生分支的机制

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绿色荧光蛋白(GFP)标记的DivIVA位于菌丝分支的末端。</p>
链霉菌产生大多数临床上有用的抗生素，然而迄今为止，我们仍然还没有完全理解它们是如何生长的。在一项新研究中，博士研究生Antje Hempel通过解决出这种链霉菌菌丝如何和为何产生分支而加深我们理解它们的生长方式。

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链霉菌通常都生活土壤中，依靠分解植物物质而生存，而且它们是通过长出一个菌丝分支网络来实现这点的。它们产生大量不同的酶从而能够利用不同的物质来源来促进它们的代谢，而且它们也产生保护性化合物。这些化合物因能够被用作抗生素和其他药物而得到很好的研究，但是这种细菌实际上是如何生长的，却一直是一个谜。  

相比于其他细菌物种，链霉菌菌丝分支生长更加类似于真菌。而且它们的细胞从末端生长，而不是常见的细菌生长方式：细菌在细胞中间伸长，然而很少有研究小组研究过这种类型的极性生长。

在此之前，Klas Flärdh博士证实极性生长依赖一种蛋白DivIVA：这种蛋白在生长末端堆积并指导细胞壁合成。根据一篇发表在<em>PLoS Computational Biology</em>期刊上的论文，Antje和来自英国约翰英纳斯中心(John Innes Centre)和瑞典隆德大学(Lund University)的同事们发现了分支位点是如何被选择的和分支化(branching, 即产生分支)是如何启动的。DivIVA积累到极点(focus)之中，而分支化就是从极点处开始启动的。Antje发现这些DivIVA极点并不是自动形成的，而是当生长末端向外延伸时，从现存的极点上分裂下来的，并且位于细胞壁侧面的后方。随后，Antje与约翰英纳斯中心生物学者David Richards和Martin Howard合作而构建出这种系统如何工作的数学模型。
<p align="center"><img src="http://www.bioon.com/biology/UploadFiles/201208/2012080922390820.jpg" alt="" width="501" height="129" border="0" />
一系列延时拍摄图片显示未来的分支位点是如何被标记的。一个小的子极点从末端极点上分裂下来，且位于细胞壁侧面的后方，随后它的大小持续增加，最终导致一个新的分支产生。DivIVA用绿色荧光蛋白加以标记，图片来自(<em>PLoS Computational Biology</em> 8(3): e1002423)</p>
极点能够分裂并产生子极点(daughter focus)，其中子极点通常大约为原始极点大小的10%。子极点的大小持续增加，直到它达到一个临界值时，它就能够触发链霉菌菌丝产生一个新的分支。末端到分支的距离是由子极点达到临界值时所花费的时间所决定的，而分支的数量依赖于极点分裂的次数。Antje在实验中努力测量这些因素，从而证实了这个数学模型所预测的结果。

这个模型也能预测罕见的事件发生，即末端极点分裂为两个大小几乎相同的子极点，这两个子极点足够大而能够触发链霉菌菌丝立即产生分支。在实验中，研究人员也精准地观察到这种分裂，从而直接在生长末端产生分支，进而证实该模型的预测结果。

这种模型也解释了新的分支如何产生，但是它也让人们产生疑问：链霉菌是否能够控制它的分支化，如果能，又是如何控制的。

如今，在一项发表在<em>PNAS</em>期刊的新研究中，Antje证实这种分支化过程是如何受到调节的。她发现DivIVA是由磷酸化控制的，并鉴定出相应的特异性激酶。在正常生长期间，只能观察到低水平的DivIVA磷酸化。但是当利用细胞壁合成抑制剂阻断末端生长时，这会触发DivIVA磷酸化，从而改变链霉菌菌丝分支产生模式。这些发现提示着，当链霉菌遇到生长障碍时，它就重新安排它的菌丝分支产生模式。

本文编译自<a href="http://phys.org/news/2012-08-bacteria.html" target="_blank">Bacteria branch out</a>
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<a title="" href="http://dx.doi.org/10.1371/journal.pcbi.1002423" target="_blank">doi: 10.1371/journal.pcbi.1002423</a>
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<br/><strong>Mechanistic basis of branch-site selection in filamentous bacteria</strong><br/>


David M. Richards1#, Antje M. Hempel1,2#, Klas Flärdh2*, Mark J. Buttner1, Martin Howard

Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed.

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<a title="" href="http://dx.doi.org/10.1073/pnas.1207409109" target="_blank">doi: 10.1073/pnas.1207409109</a>
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<br/><strong>The Ser/Thr protein kinase AfsK regulates polar growth and hyphal branching in the filamentous bacteria Streptomyces</strong><br/>


Antje M. Hempela,b, Stuart Cantlaya,1, Virginie Mollec, Sheng-Bing Wanga,2, Mike J. Naldrettb, Jennifer L. Parkerb, David M. Richardsb, Yong-Gyun Jungb, Mark J. Buttnerb, and Klas Flärdh

In cells that exhibit apical growth, mechanisms that regulate cell polarity are crucial for determination of cellular shape and for the adaptation of growth to intrinsic and extrinsic cues. Broadly conserved pathways control cell polarity in eukaryotes, but less is known about polarly growing prokaryotes. An evolutionarily ancient form of apical growth is found in the filamentous bacteria Streptomyces, and is directed by a polarisome-like complex involving the essential protein DivIVA. We report here that this bacterial polarization machinery is regulated by a eukaryotic-type Ser/Thr protein kinase, AfsK, which localizes to hyphal tips and phosphorylates DivIVA. During normal growth, AfsK regulates hyphal branching by modulating branch-site selection and some aspect of the underlying polarisome-splitting mechanism that controls branching of Streptomyces hyphae. Further, AfsK is activated by signals generated by the arrest of cell wall synthesis and directly communicates this to the polarisome by hyperphosphorylating DivIVA. Induction of high levels of DivIVA phosphorylation by using a constitutively active mutant AfsK causes disassembly of apical polarisomes, followed by establishment of multiple hyphal branches elsewhere in the cell, revealing a profound impact of this kinase on growth polarity. The function of AfsK is reminiscent of the phoshorylation of polarity proteins and polarisome components by Ser/Thr protein kinases in eukaryotes.

<br/>来源：生物谷

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