Kieckhöfer Emilia, Günzler Julia, Matthiessen Peter A, Ebert Lena K, Klausen Christina, Wachten Dagmar, Cetiner Metin, Liebau Max C, Benzing Thomas, May-Simera Helen, Schermer Bernhard
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
bioRxiv. 2025 Jun 17:2024.03.07.583949. doi: 10.1101/2024.03.07.583949.
Primary cilia dysfunction underlies a group of severe disorders known as ciliopathies. These include Bardet-Biedl syndrome (BBS), which is caused by mutations in BBS genes encoding for components of ciliary protein complexes essential for the assembly and maintenance of primary cilia. As in most ciliopathies, a hallmark feature of BBS is the development of cystic kidney disease. However, the molecular mechanisms linking ciliary dysfunction to cystogenesis remain incompletely understood. Here, we show that mice develop late-onset cystic kidney disease accompanied by increased regulated cell death and fibrosis. While the number and length of cilia are not affected, loss of BBS8 reduces K40 acetylation of α-tubulin within primary cilia, compromising ciliary stability. Notably, proteomic analysis revealed a significant upregulation of histone deacetylase HDAC2 in kidneys, which we confirmed in mouse embryonic fibroblasts (MEFs) and in urine-derived renal epithelial cells (URECs) from a BBS8 patient. We further demonstrate the protein interaction between BBS8 and HDAC2, implicating a disrupted BBS8-HDAC2 regulatory axis in disease pathogenesis. Consistent with a role of excessive HDAC2 activity in the BBS8 deficient cells, pharmacological inhibition of HDAC2 restored tubulin acetylation in BBS8 urine-derived cells. Thus, modulation of HDAC2 activity may represent a strategy to alter ciliary stability which could explain positive effects of class I specific HDAC inhibitors in models of cystic kidney disease.
原发性纤毛功能障碍是一组称为纤毛病的严重疾病的基础。这些疾病包括巴德-比德尔综合征（BBS），它是由BBS基因突变引起的，这些基因编码对原发性纤毛的组装和维持至关重要的纤毛蛋白复合物的成分。与大多数纤毛病一样，BBS的一个标志性特征是囊性肾病的发展。然而，将纤毛功能障碍与囊肿形成联系起来的分子机制仍未完全了解。在这里，我们表明，小鼠会发展为迟发性囊性肾病，并伴有调节性细胞死亡增加和纤维化。虽然纤毛的数量和长度不受影响，但BBS8的缺失会降低原发性纤毛内α-微管蛋白的K40乙酰化，损害纤毛稳定性。值得注意的是，蛋白质组学分析显示，BBS8基因敲除小鼠肾脏中的组蛋白去乙酰化酶HDAC2显著上调，我们在BBS8基因敲除小鼠胚胎成纤维细胞（MEFs）和一名BBS8患者的尿源性肾上皮细胞（URECs）中证实了这一点。我们进一步证明了BBS8与HDAC2之间的蛋白质相互作用，暗示BBS8-HDAC2调节轴的破坏在疾病发病机制中起作用。与HDAC2活性过高在BBS8缺陷细胞中的作用一致，HDAC2的药理学抑制恢复了BBS8尿源性细胞中的微管蛋白乙酰化。因此，调节HDAC2活性可能代表一种改变纤毛稳定性的策略，这可以解释I类特异性HDAC抑制剂在囊性肾病模型中的积极作用。
