Coveney Clarissa R, Collins Isabella, Mc Fie Megan, Chanalaris Anastasios, Yamamoto Kazuhiro, Wann Angus K T
Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute, Nuffield Department for Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
FASEB J. 2018 Jun 19;32(12):fj201800334. doi: 10.1096/fj.201800334.
Matrix protease activity is fundamental to developmental tissue patterning and remains influential in adult homeostasis. In cartilage, the principal matrix proteoglycan is aggrecan, the protease-mediated catabolism of which defines arthritis; however, the pathophysiologic mechanisms that drive aberrant aggrecanolytic activity remain unclear. Human ciliopathies exhibit altered matrix, which has been proposed to be the result of dysregulated hedgehog signaling that is tuned within the primary cilium. Here, we report that disruption of intraflagellar transport protein 88 (IFT88), a core ciliary trafficking protein, increases chondrocyte aggrecanase activity in vitro. We find that the receptor for protease endocytosis in chondrocytes, LDL receptor-related protein 1 (LRP-1), is unevenly distributed over the cell membrane, often concentrated at the site of cilia assembly. Hypomorphic mutation of IFT88 disturbs this apparent hot spot for protease uptake, increases receptor shedding, and results in a reduced rate of protease clearance from the extracellular space. We propose that IFT88 and/or the cilium regulates the extracellular remodeling of matrix-independently of Hedgehog regulation-by enabling rapid LRP-1-mediated endocytosis of proteases, potentially by supporting the creation of a ciliary pocket. This result highlights new roles for the cilium's machinery in matrix turnover and LRP-1 function, with potential relevance in a range of diseases.-Coveney, C. R., Collins, I., Mc Fie, M., Chanalaris, A., Yamamoto, K., Wann, A. K. T. Cilia protein IFT88 regulates extracellular protease activity by optimizing LRP-1-mediated endocytosis.
基质蛋白酶活性对于发育过程中的组织模式形成至关重要，并且在成体稳态中仍具有重要影响。在软骨中，主要的基质蛋白聚糖是聚集蛋白聚糖，其蛋白酶介导的分解代谢决定了关节炎；然而，驱动异常聚集蛋白聚糖分解活性的病理生理机制仍不清楚。人类纤毛病表现出基质改变，这被认为是初级纤毛内失调的刺猬信号通路的结果。在这里，我们报告说，核心纤毛运输蛋白鞭毛内运输蛋白88（IFT88）的破坏会增加体外软骨细胞聚集蛋白聚糖酶的活性。我们发现软骨细胞中蛋白酶内吞作用的受体，低密度脂蛋白受体相关蛋白1（LRP-1），在细胞膜上分布不均，通常集中在纤毛组装部位。IFT88的亚效突变扰乱了这个明显的蛋白酶摄取热点，增加了受体脱落，并导致蛋白酶从细胞外空间清除的速率降低。我们提出，IFT88和/或纤毛通过使蛋白酶能够通过LRP-1介导的快速内吞作用，可能通过支持纤毛口袋的形成，独立于刺猬信号通路调节基质的细胞外重塑。这一结果突出了纤毛机制在基质周转和LRP-1功能中的新作用，在一系列疾病中可能具有相关性。-科维尼，C.R.，柯林斯，I.，麦克菲，M.，查纳拉里斯，A.，山本，K.，万，A.K.T. 纤毛蛋白IFT88通过优化LRP-1介导的内吞作用调节细胞外蛋白酶活性。
