FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration

FOXK2 is a crucial transcription factor implicated in a wide array of biological activities and yet understanding of its molecular regulation at the level of protein turnover is limited. Here we identify that FOXK2 is sensitive to degradation by the virulent pathogens P. aeruginosa and K. pneumoniae in lung epithelia through ubiquitin-proteasomal processing. FOXK2 through its carboxyl-terminus (aa 428-478) binds the Skp-Cullin-F-box ubiquitin E3 ligase subunit FBXO24 that mediates multisite polyubiquitylation of the transcription factor resulting in its nuclear degradation. FOXK2 was detected within mitochondria and targeted depletion of the transcription factor or cellular expression of FOXK2 mutants devoid of key carboxyl-terminal domains significantly impaired mitochondrial function. In experimental bacterial pneumonia, Fbxo24 heterozygous mice exhibited preserved mitochondrial function and Foxk2 protein levels compared to wild-type littermates. The results suggest a new mode of regulatory control of mitochondrial energetics through modulation of FOXK2 cellular abundance.

叉头框K2（FOXK2）是一类关键转录因子，广泛参与诸多生物学过程，但目前学界对其蛋白质更新层面的分子调控机制仍了解有限。本研究证实，在肺上皮细胞中，强毒病原体铜绿假单胞菌（P. aeruginosa）与肺炎克雷伯菌（K. pneumoniae）可通过泛素-蛋白酶体途径介导FOXK2的降解，且FOXK2对该降解过程较为敏感。FOXK2可通过其羧基末端（氨基酸残基428-478）结合Skp-Cullin-F-box泛素E3连接酶亚基FBXO24，该亚基可介导此转录因子的多位点多泛素化，进而使其发生核降解。研究人员在线粒体中检测到了FOXK2的存在；靶向消减该转录因子，或是表达缺失关键羧基末端结构域的FOXK2突变体，均会显著损伤线粒体功能。在实验性细菌性肺炎模型中，与野生型同窝仔鼠相比，Fbxo24杂合子小鼠的线粒体功能得以保留，且Foxk2蛋白水平未出现显著下降。上述结果表明，可通过调控FOXK2的细胞丰度，实现线粒体能量代谢的全新调控方式。