Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
J Biol Chem. 2024 Jun;300(6):107359. doi: 10.1016/j.jbc.2024.107359. Epub 2024 May 10.
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 undergoes degradation in lung epithelia in the presence of the virulent pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae 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 the mitochondria and targeted depletion of the transcription factor or cellular expression of FOXK2 mutants devoid of key carboxy terminal domains significantly impaired mitochondrial function. In experimental bacterial pneumonia, Fbxo24 heterozygous mice exhibited preserved mitochondrial function and Foxk2 protein levels compared to WT littermates. The results suggest a new mode of regulatory control of mitochondrial energetics through modulation of FOXK2 cellular abundance.
FOXK2 是一种关键的转录因子，涉及广泛的生物学活性，但对其在蛋白质周转水平上的分子调控机制了解有限。在这里，我们发现，在毒力病原体铜绿假单胞菌和肺炎克雷伯菌存在的情况下，FOXK2 在肺上皮细胞中通过泛素蛋白酶体处理而降解。FOXK2 通过其羧基末端（aa 428-478）与 Skp-Cullin-F-box 泛素 E3 连接酶亚基 FBXO24 结合，介导转录因子的多位点多泛素化，导致其核降解。FOXK2 在内粒体中被检测到，并靶向敲除转录因子或细胞表达缺乏关键羧基末端结构域的 FOXK2 突变体，显著损害了线粒体功能。在实验性细菌性肺炎中，与 WT 同窝仔相比，Fbxo24 杂合子小鼠表现出保留的线粒体功能和 Foxk2 蛋白水平。结果表明，通过调节 FOXK2 细胞丰度，为线粒体能量代谢提供了一种新的调控控制模式。
