Filamentation and biofilm formation are regulated by the phase-separation capacity of network transcription factors in Candida albicans.
Filamentation and biofilm formation are regulated by the phase-separation capacity of network transcription factors in Candida albicans.
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DOI：
10.1371/journal.ppat.1011833
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发表时间：
2023-12
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
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真菌白色念珠菌的丝状和形成生物膜的能力有助于其作为医院获得性感染的主要原因的负担。生物膜的形成涉及一个相互连接的转录调控网络（TRN），由9个转录因子（TF）组成，这些转录因子既与自己的调控区结合，也与其他网络TF的调控区结合。在这里，我们表明，在C。白念珠菌生物膜网络含有朊病毒样结构域（PrLD），其与形成相分离的冷凝物的能力有关。在四个生物膜TF中构建PrLD突变体揭示了这些结构域对于C.白色念珠菌此外，生物膜PrLD促进在活细胞的细胞核中形成相分离的缩合物，并且消除相分离的PrLD突变（例如去除芳香族残基）也防止生物膜形成。生物膜TF缩合物可以通过PrLD-PrLD相互作用选择性地募集其他TF，并且可以共募集RNA聚合酶II，这意味着在活性转录复合物的组装中形成缩合物。最后，我们表明，PrLD突变，阻止生物膜TF的相分离，也防止在体内模型中的胃肠道定植。总之，这些研究将转录缩合物与C.白色念珠菌，并强调如何针对PrLD-PrLD相互作用可以防止这种物种的发病机制。真菌C.白色念珠菌是威胁生命的感染的普遍原因，这在很大程度上是由于其在生物或非生物表面上形成药物耐受性生物膜的能力。生物膜的形成是由九个TF组成的网络控制的，这些TF联合作用以调节它们自身的表达以及下游基因的表达。我们发现，九个主生物膜TF中的七个含有PrLD，这些结构域先前已被证明可以促进相分离成致密相以及更稀的周围相。重要的是，通过选择PrLD残基的突变破坏TF的相分离能力在体外和宿主定殖期间阻断TF功能。PrLD还促进TF与RNA聚合酶II的相互作用，表明它们可以招募细胞转录机制的关键组分。因此，我们提出TF PrLD是C的积分。白念珠菌生物膜的形成是由于它们促进蛋白质-蛋白质相互作用和相分离的能力，并且这些复合物的协调组装驱动基因表达程序。
The ability of the fungus Candida albicans to filament and form biofilms contributes to its burden as a leading cause of hospital-acquired infections. Biofilm development involves an interconnected transcriptional regulatory network (TRN) consisting of nine transcription factors (TFs) that bind both to their own regulatory regions and to those of the other network TFs. Here, we show that seven of the nine TFs in the C. albicans biofilm network contain prion-like domains (PrLDs) that have been linked to the ability to form phase-separated condensates. Construction of PrLD mutants in four biofilm TFs reveals that these domains are essential for filamentation and biofilm formation in C. albicans. Moreover, biofilm PrLDs promote the formation of phase-separated condensates in the nuclei of live cells, and PrLD mutations that abolish phase separation (such as the removal of aromatic residues) also prevent biofilm formation. Biofilm TF condensates can selectively recruit other TFs through PrLD-PrLD interactions and can co-recruit RNA polymerase II, implicating condensate formation in the assembly of active transcriptional complexes. Finally, we show that PrLD mutations that block the phase separation of biofilm TFs also prevent filamentation in an in vivo model of gastrointestinal colonization. Together, these studies associate transcriptional condensates with the regulation of filamentation and biofilm formation in C. albicans, and highlight how targeting of PrLD-PrLD interactions could prevent pathogenesis by this species. The fungus C. albicans is a prevalent cause of life-threatening infections due, in large part, to its ability to form drug-recalcitrant biofilms on biotic or abiotic surfaces. Biofilm formation is controlled by a network of nine TFs that act in combination to regulate their own expression as well as that of downstream genes. We show that seven of the nine master biofilm TFs contain PrLDs, domains that have previously been shown to promote phase separation into a dense phase together with a more dilute surrounding phase. Importantly, disruption of the phase separation capacity of TFs by mutation of select PrLD residues blocks TF function both in vitro and during host colonization. PrLDs also promote the interaction of TFs with RNA polymerase II indicating that they can recruit key components of the cell’s transcriptional machinery. We therefore propose that TF PrLDs are integral to C. albicans biofilm formation due to their ability to promote protein-protein interactions and phase separation, and that the coordinated assembly of these complexes drives gene expression programs.
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影响因子：
7.7
作者：
Keenen MM;Brown D;Brennan LD;Renger R;Khoo H;Carlson CR;Huang B;Grill SW;Narlikar GJ;Redding S
通讯作者：
Redding S
影响因子：
64.5
作者：
Feric M;Vaidya N;Harmon TS;Mitrea DM;Zhu L;Richardson TM;Kriwacki RW;Pappu RV;Brangwynne CP
通讯作者：
Brangwynne CP
影响因子：
64.5
作者：
Boija A;Klein IA;Sabari BR;Dall'Agnese A;Coffey EL;Zamudio AV;Li CH;Shrinivas K;Manteiga JC;Hannett NM;Abraham BJ;Afeyan LK;Guo YE;Rimel JK;Fant CB;Schuijers J;Lee TI;Taatjes DJ;Young RA
通讯作者：
Young RA
影响因子：
19
作者：
Boeynaems S;Alberti S;Fawzi NL;Mittag T;Polymenidou M;Rousseau F;Schymkowitz J;Shorter J;Wolozin B;Van Den Bosch L;Tompa P;Fuxreiter M
通讯作者：
Fuxreiter M
DOI：
10.1073/pnas.152101299
发表时间：
2002-07-09
影响因子：
11.1
作者：
Chai, YH;Shao, JQ;Paulson, HL
通讯作者：
Paulson, HL