Departamento Ciencias Biomédicas, Universidad de Extremadura, Badajoz, Spain.
PLoS Pathog. 2012;8(5):e1002683. doi: 10.1371/journal.ppat.1002683. Epub 2012 May 10.
In nature, many microorganisms form specialized complex, multicellular, surface-attached communities called biofilms. These communities play critical roles in microbial pathogenesis. The fungal pathogen Candida albicans is associated with catheter-based infections due to its ability to establish biofilms. The transcription factor Bcr1 is a master regulator of C. albicans biofilm development, although the full extent of its regulation remains unknown. Here, we report that Bcr1 is a phosphoprotein that physically interacts with the NDR kinase Cbk1 and undergoes Cbk1-dependent phosphorylation. Mutating the two putative Cbk1 phosphoacceptor residues in Bcr1 to alanine markedly impaired Bcr1 function during biofilm formation and virulence in a mouse model of disseminated candidiasis. Cells lacking Cbk1, or any of its upstream activators, also had reduced biofilm development. Notably, mutating the two putative Cbk1 phosphoacceptor residues in Bcr1 to glutamate in cbk1Δ cells upregulated the transcription of Bcr1-dependent genes and partially rescued the biofilm defects of a cbk1Δ strain. Therefore, our data uncovered a novel role of the NDR/LATS kinase Cbk1 in the regulation of biofilm development through the control of Bcr1.
在自然界中，许多微生物形成专门的复杂、多细胞、附着在表面的群落，称为生物膜。这些群落对微生物发病机制起着至关重要的作用。真菌病原体白色念珠菌因其形成生物膜的能力而与基于导管的感染有关。转录因子 Bcr1 是 C. albicans 生物膜发育的主要调节剂，尽管其调控的全部范围尚不清楚。在这里，我们报告说 Bcr1 是一种磷酸化蛋白，它与 NDR 激酶 Cbk1 相互作用，并发生 Cbk1 依赖性磷酸化。将 Bcr1 中的两个假定的 Cbk1 磷酸化接受残基突变为丙氨酸，明显损害了生物膜形成过程中的 Bcr1 功能，并在播散性念珠菌病的小鼠模型中降低了毒力。缺乏 Cbk1 或其任何上游激活剂的细胞也减少了生物膜的发育。值得注意的是，在 cbk1Δ细胞中将 Bcr1 中的两个假定的 Cbk1 磷酸化接受残基突变为谷氨酸，上调了 Bcr1 依赖性基因的转录，并部分挽救了 cbk1Δ 菌株的生物膜缺陷。因此，我们的数据揭示了 NDR/LATS 激酶 Cbk1 通过控制 Bcr1 在生物膜发育调控中的新作用。
