Assembly of a heptameric STRIPAK complex is required for coordination of light-dependent multicellular fungal development with secondary metabolism in Aspergillus nidulans
Assembly of a heptameric STRIPAK complex is required for coordination of light-dependent multicellular fungal development with secondary metabolism in Aspergillus nidulans
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DOI：
10.1371/journal.pgen.1008053
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发表时间：
2019-03-01
期刊：
影响因子：
4.5
通讯作者：
Bayram, Ozgur
中科院分区：
文献类型：
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作者：
Elramli, Nadia;Karahoda, Betim;Bayram, Ozgur
真核纹状体形成纹状体相互作用磷酸酶和激酶（STRIPAK）复合物，其控制许多细胞过程，包括发育、细胞运输、信号转导、干细胞分化和心脏功能。然而，复杂的组装及其在应激反应中的作用的详细知识目前知之甚少。在这里，我们发现了六个条纹蛋白（StrA）相互作用的蛋白质（Sips），形成一个七聚体复合物的丝状真菌构巢曲霉。该复合物分别由纹状体支架StrA、Mob 3型激酶共激活因子SipA、SIKE样蛋白SipB、STRIP 1/2同源物SipC、SLMAP相关蛋白SipD以及催化和调节磷酸酶2A亚基SipE（PpgA）和SipF组成。复杂组分的单和双缺失导致多细胞光依赖性真菌发育、次级代谢产物产生（例如真菌毒素Sterigmatocystin）的丧失和应激反应的降低。sipA（Mob 3）缺失对strA缺失是上位性的，其通过抑制由缺乏条纹蛋白引起的所有缺陷。在营养生长期间建立并在光和暗发育的早期维持的STRIPAK复合物主要在支架StrA存在下在核膜上形成。支架的丢失揭示了三个STRIPAK亚复合物：（I）SipA仅与StrA相互作用，（II）SipB-SipD被发现作为异源二聚体，（III）SipC、SipE和SipF作为异源三聚体复合物存在。STRIPAK复合物是异源三聚体VeA-VelB-LaeA复合物适当表达所必需的，该复合物协调真菌发育和次级代谢。此外，在没有应激条件下，STRIPAK复合物通过促进MpkB的磷酸化和限制MpkC的核穿梭来调节两个重要的MAPK途径。SipB in A. nidulans类似于人类IKK-kB抑制蛋白（SIKE），其抑制哺乳动物的抗病毒反应，而天鹅绒家族蛋白显示出与哺乳动物促炎性NF-κ B蛋白的强烈相似性。这些蛋白质在A. nidulans进一步加强了假设，哺乳动物和真菌使用类似的蛋白质为他们的免疫反应和次级代谢产物productions.Author摘要多亚基STRIPAK复合物已被研究从酵母到人类，并发挥了一系列的作用，从细胞周期阻滞，子实体的形成神经元的功能。STRIPAK复合物的分子组装及其在应激反应中的作用尚未得到充分证实。真菌，估计有150万成员是人类的朋友和敌人，作为病原体，天然产物和酶生产者。在丝状真菌构巢曲霉中，我们发现了一个由三个亚复合物组成的七聚体STRIPAK核心复合物，它位于核膜上，协调光依赖性真菌发育，次生代谢和胁迫反应的信号流入。STRIPAK复合物通过促进其磷酸化或限制其在静息条件下的核定位来控制两种主要的有丝分裂原活化蛋白激酶（MAPK）信号通路的活性。这些发现为真菌如何通过使用核膜上的多聚体支架蛋白复合物来控制不同的下游途径来管理信号流入奠定了基础。
Eukaryotic striatin forms striatin-interacting phosphatase and kinase (STRIPAK) complexes that control many cellular processes including development, cellular transport, signal transduction, stem cell differentiation and cardiac functions. However, detailed knowledge of complex assembly and its roles in stress responses are currently poorly understood. Here, we discovered six striatin (StrA) interacting proteins (Sips), which form a heptameric complex in the filamentous fungus Aspergillus nidulans. The complex consists of the striatin scaffold StrA, the Mob3-type kinase coactivator SipA, the SIKE-like protein SipB, the STRIP1/2 homolog SipC, the SLMAP-related protein SipD and the catalytic and regulatory phosphatase 2A subunits SipE (PpgA), and SipF, respectively. Single and double deletions of the complex components result in loss of multicellular light-dependent fungal development, secondary metabolite production (e.g. mycotoxin Sterigmatocystin) and reduced stress responses. sipA (Mob3) deletion is epistatic to strA deletion by supressing all the defects caused by the lack of striatin. The STRIPAK complex, which is established during vegetative growth and maintained during the early hours of light and dark development, is mainly formed on the nuclear envelope in the presence of the scaffold StrA. The loss of the scaffold revealed three STRIPAK subcomplexes: (I) SipA only interacts with StrA, (II) SipB-SipD is found as a heterodimer, (III) SipC, SipE and SipF exist as a heterotrimeric complex. The STRIPAK complex is required for proper expression of the heterotrimeric VeA-VelB-LaeA complex which coordinates fungal development and secondary metabolism. Furthermore, the STRIPAK complex modulates two important MAPK pathways by promoting phosphorylation of MpkB and restricting nuclear shuttling of MpkC in the absence of stress conditions. SipB in A. nidulans is similar to human suppressor of IKK-epsilon(SIKE) protein which supresses antiviral responses in mammals, while velvet family proteins show strong similarity to mammalian proinflammatory NF-KB proteins. The presence of these proteins in A. nidulans further strengthens the hypothesis that mammals and fungi use similar proteins for their immune response and secondary metabolite production, respectively.Author summary The multisubunit STRIPAK complex has been studied from yeast to human and plays a range of roles from cell-cycle arrest, fruit body formation to neuronal functions. Molecular assembly of the STRIPAK complex and its roles in stress responses are not well-documented. Fungi, with an estimated 1.5 million members are friends and foes of mankind, acting as pathogens, natural product and enzyme producers. In filamentous fungus Aspergillus nidulans, we found a heptameric STRIPAK core complex made from three subcomplexes, which sits on the nuclear envelope and coordinates signal influx for light-dependent fungal development, secondary metabolism and stress responses. STRIPAK complex controls activities of two major Mitogen Activated Protein Kinase (MAPK) signaling pathways through either promoting their phosphorylation or limiting their nuclear localization under resting conditions. These findings establish a basis for how fungi govern signal influx by using multimeric scaffold protein complexes on the nuclear envelope to control different downstream pathways.