Analysing the cell biology of SNX10 in endosomal sorting and signaling: implications for osteoclast function in osteopetrosis

分析 SNX10 在内体分选和信号转导中的细胞生物学：对骨石症中破骨细胞功能的影响

• 批准号: MR/L007363/1
• 负责人: Peter Cullen
• 金额: $ 48.59万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL007363%2F1
• 关键词: Analysing; cell; biology; SNX10; endosomal

All human cells are composed of an outer boundary that is defined by a complex mixture of protein and lipids called the plasma membrane. This encircles a fluid filled 3-dimensional space, termed the cytosol, which contains additional membrane-enriched compartments each composed of a unique combination of proteins and lipids. For cells to functional normally, proteins and lipids must be efficiently transported to the correct membrane-enriched compartment within this maze of membranes. Not surprisingly, if such transport is perturbed, so that the wrong proteins and lipids are delivered to the incorrect membrane-enriched compartment, cell function can be adversely affected which in turn leads to the development of various diseases. Establishing the mechanisms through which cells achieve regulated protein and lipid transport is therefore a major challenge in cell biology with direct implication for our understanding of human disease.For over 10 years our laboratory has focused on describing the mechanistic details that control regulated transport of proteins and lipids within a specific aspect of the cell's membranous maze termed the endocytic network. In particular, we have studied a family of ancient, evolutionary conserved proteins, the sorting nexins. Within this family we have extensively analysed the function of retromer complexes, and this is generating new insight into the perturbed function of the endosomal network during cell infection by various pathogens, as well as a variety of diseases including Alzheimer's disease and Parkinson's disease.In the current proposal we seek to utilize our extensive experience of studying sorting nexins to define the function of sorting nexin-10 (SNX10) in the regulation of bone re-modeling. This stems from research showing that mutations in SNX10 are linked with autosomal recessive osteopetrosis, a genetically heterogenous disorder caused by reduced bone resorption by a specific class of cells termed osteoclasts. However, at present we do not understand the basic function of SNX10, and hence have a very limited appreciation of why its mutation leads to this debilitating disease.Our proposed research will address the following questions:1). Is SNX10 required for endosomal sorting of RANK and downstream RANKL signaling?2). Is the cell surface expression of other receptors also regulated by SNX10?3). What are the molecular details of SNX10-mediated endosomal sorting?4). Do the molecular details of SNX10-mediated endosomal sorting generate further insight into diseases of bone homeostasis?Overall, data derived from the proposed research, which will be disseminated through peer-review publications and oral presentation at international meetings, will define the role of SNX10 in osteoclast function, knowledge that will achieve a greater appreciation of the cellular defects that lead to osteopetrosis and possibly other related bone diseases. Longer term, the research may provide a rationale for therapeutic intervention in patients carrying the SNX10 mutations and other osteopetrosis-linked mutations.

所有人类细胞均由外边界组成，外边界由蛋白质和脂质的复杂混合物定义，称为质膜。这环绕着填充的三维空间，称为细胞质，其中包含额外的膜含有膜的隔室，每个隔室由蛋白质和脂质的独特组合组成。对于细胞正常功能，必须将蛋白质和脂质有效地转移到这种膜迷宫中的富含膜的隔室中。毫不奇怪，如果这种转运受到干扰，因此将错误的蛋白质和脂质传递到了不正确的膜含量的室，则细胞功能可能会受到不利影响，从而导致各种疾病的发展。因此，建立细胞实现调节蛋白质和脂质转运的机制是细胞生物学的主要挑战，对我们对人类疾病的理解有直接的影响。在10多年中，我们的实验室专注于描述机械细节，这些细节控制了控制细胞膜膜的特定方面的蛋白质和脂质的转运，这些蛋白质和脂质被称为膜状膜的膜状网络。特别是，我们研究了一个古老的，进化保守的蛋白质，即分类蛋白。 Within this family we have extensively analysed the function of retromer complexes, and this is generating new insight into the perturbed function of the endosomal network during cell infection by various pathogens, as well as a variety of diseases including Alzheimer's disease and Parkinson's disease.In the current proposal we seek to utilize our extensive experience of studying sorting nexins to define the function of sorting nexin-10 (SNX10)在调节骨重新模块的调节中。这源于研究表明，SNX10中的突变与常染色体隐性骨质造成术有关，这是由于特定类型的破骨细胞的特定细胞减少骨骼吸收而引起的遗传异源性疾病。但是，目前我们不了解SNX10的基本功能，因此对为什么它的突变导致这种使人衰弱的疾病的理解非常有限。我们的拟议研究将解决以下问题：1）。秩和下游RANKL信号传导的内体分类需要SNX10吗？2）。其他受体的细胞表面表达是否也受SNX10？3的调节。 SNX10介导的内体分选的分子细节是什么？4）。 SNX10介导的内体分类的分子细节是否会进一步了解骨骼稳态的疾病？总体上是从拟议的研究中得出的数据，这些数据将通过同行评估的出版物和国际会议上的口头呈现来分散，这将使SNX10在Osteoclast功能中的作用更大，以至于依赖于SNX10的作用，以至于有影响力，以至于有影响力的依赖性，以至于有影响力的影响力。骨骼疾病。从长远来看，这项研究可能为携带SNX10突变和其他骨质疏松症与与其他骨质疏松性突变的患者提供治疗干预的理由。

项目成果

Endoplasmic Reticulum-Endosome Contact Sites: Specialized Interfaces for Orchestrating Endosomal Tubule Fission?

• DOI: 10.1021/acs.biochem.8b01176
• 发表时间: 2018-12-11
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Daly, James L.;Cullen, Peter J.
• 通讯作者: Cullen, Peter J.

Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation.

• DOI: 10.1038/s41467-023-39643-7
• 发表时间: 2023-07-03
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Calcagni, Alessia;Staiano, Leopoldo;Zampelli, Nicolina;Minopoli, Nadia;Herz, Niculin J.;Di Tullio, Giuseppe;Huynh, Tuong;Monfregola, Jlenia;Esposito, Alessandra;Cirillo, Carmine;Bajic, Aleksandar;Zahabiyon, Mahla;Curnock, Rachel;Polishchuk, Elena;Parkitny, Luke;Medina, Diego Luis;Pastore, Nunzia;Cullen, Peter J.;Parenti, Giancarlo;De Matteis, Maria Antonietta;Grumati, Paolo;Ballabio, Andrea
• 通讯作者: Ballabio, Andrea

Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health.

• DOI: 10.1038/s41467-023-38719-8
• 发表时间: 2023-05-29
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Daly, James L.;Danson, Chris M.;Lewis, Philip A.;Zhao, Lu;Riccardo, Sara;Di Filippo, Lucio;Cacchiarelli, Davide;Lee, Daehoon;Cross, Stephen J.;Heesom, Kate J.;Xiong, Wen-Cheng;Ballabio, Andrea;Edgar, James R.;Cullen, Peter J.
• 通讯作者: Cullen, Peter J.

Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome.

• DOI: 10.1016/j.cell.2023.04.003
• 发表时间: 2023-05-11
• 期刊: CELL
• 影响因子: 64.5
• 作者: Healy, Michael D.;McNally, Kerrie E.;Butkovic, Rebeka;Chilton, Molly;Kato, Kohji;Sacharz, Joanna;McConville, Calum;Moody, Edmund R. R.;Shaw, Shrestha;Planelles-Herrero, Vicente J.;Yadav, Sathish K. N.;Ross, Jennifer;Borucu, Ufuk;Palmer, Catherine S.;Chen, Kai-En;Croll, Tristan I.;Hall, Ryan J.;Caruana, Nikeisha J.;Ghai, Rajesh;Nguyen, Thi H. D.;Heesom, Kate J.;Saitoh, Shinji;Berger, Imre;Schaffitzel, Christiane;Williams, Tom A.;Stroud, David A.;Derivery, Emmanuel;Collins, Brett M.;Cullen, Peter J.
• 通讯作者: Cullen, Peter J.

Sorting nexin 5 mediates virus-induced autophagy and immunity.

• DOI: 10.1038/s41586-020-03056-z
• 发表时间: 2021-01
• 期刊: Nature
• 影响因子: 64.8
• 作者: Dong X;Yang Y;Zou Z;Zhao Y;Ci B;Zhong L;Bhave M;Wang L;Kuo YC;Zang X;Zhong R;Aguilera ER;Richardson RB;Simonetti B;Schoggins JW;Pfeiffer JK;Yu L;Zhang X;Xie Y;Schmid SL;Xiao G;Gleeson PA;Ktistakis NT;Cullen PJ;Xavier RJ;Levine B
• 通讯作者: Levine B