Phosphorylation of MIF by PIP4K2a is necessary for cilia biogenesis.
Phosphorylation of MIF by PIP4K2a is necessary for cilia biogenesis.
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DOI：
10.1038/s41419-023-06323-9
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发表时间：
2023-12-05
影响因子：
9
通讯作者：
Li, Xiaogang
中科院分区：
文献类型：
--
作者：
Zhang, Lu;Zhang, Hongbing;Agborbesong, Ewud;Zhou, Julie Xia;Li, Xiaogang
初级纤毛是基于微管的细胞器，在发育和组织稳态中起重要作用。巨噬细胞移动抑制因子（MIF）是一种分泌型细胞因子，在多种人类疾病的发病机制中起重要作用，包括癌症和常染色体显性遗传性多囊肾病（ADPKD）。与其他细胞因子不同，细胞内MIF的独特功能特征已经出现。在这项研究中，我们发现，MIF是本地化，并在中心粒的近端形成一个环状结构，它通过影响1）TTBK 2的招募到基体和CP 110从母亲中心粒，2）在中心粒卫星的CEP 290的积累，3）鞭毛内运输（IFT）相关蛋白的运输来调节纤毛的生物发生。我们还发现，MIF作为一种新的转录因子，通过与纤毛发生相关基因的启动子结合来调控这些基因的表达。MIF还结合染色质并调节参与多种稳态信号传导途径的基因的转录。我们确定磷脂酰肌醇-5-磷酸4-激酶2 α（PIP 4K 2a）作为MIF的上游调节因子，其与MIF在S91处相互作用并使其磷酸化，以增加其与14-3-3 β的相互作用，从而导致其核转位和转录调节。这项研究表明，MIF是纤毛生物发生的关键球员和一种新的转录调节因子的稳态，这推进了我们的理解，MIF是如何能够执行几个不重叠的功能。
Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Macrophage migration inhibitory factor (MIF) has long been recognized as a secreted cytokine in the pathogenesis of various human diseases, including cancer and autosomal dominant polycystic kidney disease (ADPKD). Unlike other cytokines, unique functional characteristics of intracellular MIF have emerged. In this study, we show that MIF is localized and formed a ring like structure at the proximal end of centrioles, where it regulates cilia biogenesis through affecting 1) the recruitment of TTBK2 to basal body and the removal of CP110 from mother centriole, 2) the accumulation of CEP290 at centriolar satellites, and 3) the trafficking of intraflagellar transport (IFT) related proteins. We also show that MIF functions as a novel transcriptional factor to regulate the expression of genes related to ciliogenesis via binding on the promotors of those genes. MIF also binds chromatin and regulates transcription of genes involved in diverse homeostatic signaling pathways. We identify phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2a) as an upstream regulator of MIF, which interacts with and phosphorylates MIF at S91 to increase its interaction with 14-3-3ζ, resulting in its nuclear translocation and transcription regulation. This study suggests that MIF is a key player in cilia biogenesis and a novel transcriptional regulator in homeostasis, which forward our understanding of how MIF is able to carry out several nonoverlapping functions.
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