Autophagic flux regulation by the cholesterol/H+ antiporter PTCH1

胆固醇/H 逆向转运蛋白 PTCH1 调节自噬流

基本信息

批准号：
BB/S01716X/1
负责人：
Natalia Riobo-Del Galdo
金额：
$ 58.82万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS01716X%2F1
关键词：
Autophagic flux regulation cholesterol H+

项目摘要

Development of a fertilized egg into a properly formed embryo requires a number of signals that perfectly orchestrate the formation of tissues and organs. One of those important signalling events is the so-called "Hedgehog" pathway that when absent provokes very serious congenital defects incompatible with life. Conversely, excessive activity of the Hedgehog pathway after birth is a common cause of childhood brain tumours and adult brain, skin, lung, prostate, and gut cancers. My group has contributed to the understanding of how the Hedgehog signals are perceived by cells and transmitted into different outcomes, depending on the tissue type and the context. Here, we propose to investigate a novel function of the Hedgehog pathway in regulating autophagy, the "self-eating" behaviour of cells. We found that the Hedgehog receptor PTCH1, a tumour suppressor, inhibits autophagy. Cells normally feed themselves from available nutrients; however, in conditions of starvation like those encountered by tumour cells that grow faster that the vasculature that nourishes them, cells degrade part of their contents to survive. Autophagy is essential for cancer cells survival. We will investigate how the Hedgehog pathway regulates autophagy at the molecular level. We will build onto our recent publication that shows that interaction between the C-terminal domain of PTCH1 and ATG101 is necessary for inhibition of autophagy, characterised by reduced number of acidic vesicles where degradation occurs. We propose that PTCH1 acts as a transporter, dissipating the proton gradient of those vesicles (autolysosomes) by a mechanism coupled to cholesterol transport. We will test this hypothesis and will investigate if this function of PTCH1 is lost by mutations of the C-terminal domain frequently found in cancer. We hope that our findings will increase the knowledge on new targets for cancer therapy and will reveal new ways in which cells adapt and survive to different stressors.

将受精卵的卵发育成正确形成的胚胎需要许多信号，这些信号完美地策划了组织和器官的形成。这些重要的信号事件之一是所谓的“刺猬”途径，当缺乏非常严重的先天性缺陷时，与生命不相容。相反，出生后刺猬途径的活动过多是儿童脑肿瘤和成人脑，皮肤，肺，前列腺和肠癌的常见原因。我的小组有助于理解细胞如何看待刺猬信号并根据组织类型和背景传播到不同的结果。在这里，我们建议研究刺猬途径在调节自噬的新功能，即细胞的“自食”行为。我们发现刺猬受体PTCH1是一种抑制肿瘤，抑制了自噬。细胞通常从可用的营养素中养育自己；但是，在饥饿的条件下，就像肿瘤细胞遇到的那些生长速度快于滋养它们的脉管系统，细胞会使部分含量的一部分降解以生存。自噬对于癌细胞存活至关重要。我们将研究刺猬途径如何调节分子水平的自噬。我们将建立在最近的出版物上，该出版物表明，PTCH1和ATG101的C末端结构域之间的相互作用对于抑制自噬是必要的，其特征在于发生降解的酸性囊泡数量减少。我们建议PTCH1充当转运蛋白，通过与胆固醇转运的机制散发这些囊泡（自溶剂体）的质子梯度。我们将检验该假设，并将研究PTCH1的这种功能是否因癌症经常发现的C末端结构域的突变而丢失。我们希望我们的发现能够增加对癌症治疗新靶标的知识，并揭示细胞适应不同压力源的新方法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis.

DOI：
10.1371/journal.pgen.1009275
发表时间：
2021-04
期刊：
PLoS genetics
影响因子：
4.5
作者：
Mellis D;Staines KA;Peluso S;Georgiou IC;Dora N;Kubiak M;Van't Hof R;Grillo M;Farquharson C;Kinsella E;Thornburn A;Ralston SH;Salter DM;Riobo-Del Galdo NA;Hill RE;Ditzel M
通讯作者：
Ditzel M

Partial Truncation of the C-Terminal Domain of PTCH1 in Cancer Enhances Autophagy and Metabolic Adaptability.