Politechnika Wrocławska, Wydział Podstawowych Problemów Techniki, Katedra Inżynierii Biomedycznej, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Non-self Recognition in Fungi, Institut de Biochimie et de Génétique Cellulaire, UMR 5095 CNRS, Université de Bordeaux, 1 Rue Camille Saint Saëns, 33077 Bordeaux CEDEX, France.
J Mol Biol. 2020 Nov 20;432(23):6005-6027. doi: 10.1016/j.jmb.2020.10.004. Epub 2020 Oct 13.
In filamentous fungi, amyloid signaling sequences allow Nod-like receptors (NLRs) to activate downstream cell-death inducing proteins with HeLo and HeLo-like (HELL) domains and amyloid RHIM and RHIM-related motifs control immune defense pathways in mammals and flies. Herein, we show bioinformatically that analogous amyloid signaling motifs exist in bacteria. These short motifs are found at the N terminus of NLRs and at the C terminus of proteins with a domain we term BELL. The corresponding NLR and BELL proteins are encoded by adjacent genes. We identify 10 families of such bacterial amyloid signaling sequences (BASS), one of which (BASS3) is homologous to RHIM and a fungal amyloid motif termed PP. BASS motifs occur nearly exclusively in bacteria forming multicellular structures (mainly in Actinobacteria and Cyanobacteria). We analyze experimentally a subset of seven of these motifs (from the most common BASS1 family and the RHIM-related BASS3 family) and find that these sequences form fibrils in vitro. Using a fungal in vivo model, we show that all tested BASS-motifs form prions and that the NLR-side motifs seed prion-formation of the corresponding BELL-side motif. We find that BASS3 motifs show partial prion cross-seeding with mammalian RHIM and fungal PP-motifs and that proline mutations on key positions of the BASS3 core motif, conserved in RHIM and PP-motifs, abolish prion formation. This work expands the paradigm of prion amyloid signaling to multicellular prokaryotes and suggests a long-term evolutionary conservation of these motifs from bacteria, to fungi and animals.
在丝状真菌中，淀粉样信号序列允许 Nod 样受体 (NLRs) 通过 HeLo 和 HeLo 样 (HELL) 结构域激活下游诱导细胞死亡的蛋白质，而在哺乳动物和果蝇中，淀粉样 RHIM 和 RHIM 相关基序控制免疫防御途径。在此，我们通过生物信息学方法表明，类似的淀粉样信号基序也存在于细菌中。这些短基序位于 NLR 的 N 端和我们称为 BELL 的结构域的 C 端。相应的 NLR 和 BELL 蛋白由相邻基因编码。我们确定了 10 种此类细菌淀粉样信号序列（BASS），其中一种（BASS3）与 RHIM 和一种真菌淀粉样基序 PP 同源。BASS 基序几乎仅存在于形成多细胞结构的细菌中（主要在放线菌和蓝细菌中）。我们实验分析了这 7 个基序中的一部分（来自最常见的 BASS1 家族和与 RHIM 相关的 BASS3 家族），并发现这些序列在体外形成纤维。使用真菌体内模型，我们表明所有测试的 BASS 基序都形成朊病毒，并且 NLR 侧基序为相应的 BELL 侧基序的朊病毒形成提供种子。我们发现 BASS3 基序与哺乳动物 RHIM 和真菌 PP 基序具有部分朊病毒交叉播种，并且在 RHIM 和 PP 基序中保守的 BASS3 核心基序的关键位置的脯氨酸突变会破坏朊病毒的形成。这项工作将朊病毒淀粉样信号的范例扩展到多细胞原核生物，并表明这些基序从细菌、真菌到动物的长期进化保守。
