FAM134C通过自噬调节BMP信号通路的机制研究

BMP is known as one of the most important signaling axes during bone development, maintenance, and disease. A better understanding of the molecular mechanisms of BMP signaling could provide considerable insights in developing efficient approaches to treat bone defects. Here, we screened out a novel protein FAM134C by mass spectrometry, which interacted with BMPs type I receptors, ALK3. And it can inhibit BMP signaling by decreasing the protein level of ALK3. On the other side, FAM134C contains a conserved putative LC3-interacting region, which was also found to be interaction partners of LC3. More interestingly, substitution of amino acids of LIR motif completely abolished the interaction of FAM134C with LC3 and its ability in decreasing ALK3. These data show FAM134C may be a new direct regulator of BMP signaling and identify a potential novel autophagy receptor. Since the FAM134C gene deficient mice have been reported with abnormal bone development, we hypothesized that FAM134C might regulate the BMP signaling pathway via autophagy and degrade the bone development. Autophagy is known as a degradative pathway that controls the quality and abundance of proteins and cellular organelles. However, the effect of autophagy on BMP signaling pathway has not been reported yet. Our research will clarify the molecular mechanism of FAM134C in regulation of BMP signaling pathway, evaluate the effect of selective autophagy during this regulation, and elucidate the biological function of FAM134C in vivo and in vitro. The project will provide a new perspective of BMP signaling pathway regulation, and a new foundation for therapies of bone diseases and skeletal disorders.

BMP信号是调控骨形成发育的重要信号通路，研究BMP信号的调节具有重要的生物学意义。我们通过质谱分析筛选出了一个新的蛋白FAM134C，该蛋白与BMP的I型受体ALK3相互作用，并通过降解ALK3抑制BMP信号通路。FAM134C还具有LIR结构域，能与LC3相互作用，在自噬发生时该蛋白能进入自噬小体中。更有意思的是FAM34C的LIR结构域决定了其降解ALK3的能力。有报道称FAM134C的基因型缺陷小鼠存在骨发育异常。我们推测FAM134C很可能通过自噬降解ALK3调控BMP信号通路进而影响骨发育。自噬对维持细胞和机体的稳态有着至关重要的作用，但至今未报道该过程对BMP信号通路的影响。本项目的研究将明确FAM134C调控BMP信号通路具体分子机制，证明该机制中自噬的作用，并阐明体内外FAM134C的生物学功能。本项目将为BMP信号通路的调控提供一新的视角，为骨发育疾病提供新的药物靶标。

BMP信号是胚胎发育和维持组织稳态的重要信号通路之一，该信号途径的异常会导致胚胎发育的紊乱或癌症的发生，因此对BMP信号的调节具有重要的生物学意义。目前仅报道该信号通路能够通过泛素化蛋白酶体方式降解其相关蛋白进行调控。细胞自噬是利用溶酶体降解自身细胞器和大分子物质的过程，对于维持细胞和机体的稳态有着至关重要的作用，目前自噬已报道参与了抵抗炎症、肿瘤、神经退行性变等多个重要过程。作为蛋白质降解的另一重要途径，自噬是否也参与到BMP信号通路的调控之中目前依然未知。在本项目中，我们通过质谱分析筛选出了一个新的蛋白FAM134C，该蛋白与BMP的I型受体BMPR1a相互作用，并通过降解BMPR1a抑制BMP信号通路。通过进一步研究我们发现，FAM134C具有LIR结构域，能与LC3相互作用。更有意思的是，我们发现FAM134C通过自噬过程将LC3作为桥梁将BMPR1a拉入自噬小体后进行降解。在FAM134C敲除的小鼠肠道中，由于BMP信号较强，其小肠干细胞的干性受到抑制，因此其再生能力相较于野生型小鼠弱，这一现象能够通过加入BMP信号通路抑制剂得以缓解。在斑马鱼中，过表达FAM134C会抑制BMP信号通路抑制斑马鱼的正常发育。通过本项目的研究，我们第一次证实了BMP信号通路能够通过自噬进行调控，同时找到了其调控的关键因子FAM134C。这为BMP信号通路的调控提供一新的视角，为BMP相关疾病治疗提供新的理论基础。