Caenorhabditis elegans PTR/PTCHD PTR-18 promotes the clearance of extracellular hedgehog-related protein via endocytosis.
Caenorhabditis elegans PTR/PTCHD PTR-18 promotes the clearance of extracellular hedgehog-related protein via endocytosis.
复制标题
DOI：
10.1371/journal.pgen.1009457
复制
发表时间：
2021-04
期刊：
影响因子：
4.5
通讯作者：
Fukuyama M
中科院分区：
文献类型：
--
作者：
Chiyoda H;Kume M;Del Castillo CC;Kontani K;Spang A;Katada T;Fukuyama M
信号的时空限制在动物发育和组织稳态中起着至关重要的作用。新孵化的秀丽隐杆线虫幼虫的所有干细胞和祖细胞都是静止的，能够暂停发育，直到有足够的食物供应。在这里，我们发现PTR -18编码进化上保守的补丁相关(PTR)/补丁结构域含（PTCHD）蛋白，暂时限制细胞外刺猬相关蛋白的可用性，以建立祖细胞维持静止的能力。我们发现，即使在饥饿条件下孵化的ptr-18突变幼虫，神经祖细胞也会从静止状态中退出。这种不必要的再激活依赖于一组与刺猬相关的grl基因的活性，包括grl-7。出乎意料的是，PTR-18和GRL-7在新孵化的野生型幼虫中均未表达。相反，在胚胎后期，PTR-18和GRL-7蛋白首先定位于皮下和神经祖细胞的顶膜周围，随后在孵化前被溶酶体降解。ptr-18的缺失导致GRL-7清除的显著延迟，导致该蛋白在新孵化的ptr-18突变体幼虫中保留在细胞外空间。此外，PTR-18的假定转运体活性被证明是蛋白质适当功能所必需的。这些发现不仅揭示了PTR/PTCHD在通过内吞噬介导的降解清除细胞外刺猬相关蛋白中的作用，而且还说明了在胚胎发生过程中暂时限制细胞间信号传导的失败随后会损害胚胎后祖细胞的功能。在动物体内，许多“信号”在组织和细胞之间交换，以确保健康的生长和生理状况。已知过多或过少的信号会导致各种疾病，如癌症和糖尿病。当发育中的动物没有得到足够的食物时，它们的生长速度通常会减慢。我们发现，当缺乏PTR-18蛋白的线虫在缺乏足够食物的情况下从卵中孵化出来时，它们不会适当地停止生长。分子和细胞水平的分析表明，在孵化之前，PTR-18从细胞外部到细胞内部重新摄取一种称为GRL-7的信号分子，导致GRL-7的降解。GRL-7被称为促进生长的信号分子。因此，缺乏PTR-18的蠕虫在孵化后仍含有过量的GRL-7，即使在没有充足食物的情况下也会导致不必要的生长。因此，我们的发现揭示了PTR-18在准时终止信号中的作用。人类也拥有一种名为PTCHD1的蛋白质，其结构与蠕虫的PTR-18相似，并被认为会导致自闭症谱系障碍和学习障碍。我们的发现可能为进一步了解人类PTCHD1的功能提供线索。
Spatiotemporal restriction of signaling plays a critical role in animal development and tissue homeostasis. All stem and progenitor cells in newly hatched C. elegans larvae are quiescent and capable of suspending their development until sufficient food is supplied. Here, we show that ptr-18, which encodes the evolutionarily conserved patched-related (PTR)/patched domain-containing (PTCHD) protein, temporally restricts the availability of extracellular hedgehog-related protein to establish the capacity of progenitor cells to maintain quiescence. We found that neural progenitor cells exit from quiescence in ptr-18 mutant larvae even when hatched under starved conditions. This unwanted reactivation depended on the activity of a specific set of hedgehog-related grl genes including grl-7. Unexpectedly, neither PTR-18 nor GRL-7 were expressed in newly hatched wild-type larvae. Instead, at the late embryonic stage, both PTR-18 and GRL-7 proteins were first localized around the apical membrane of hypodermal and neural progenitor cells and subsequently targeted for lysosomal degradation before hatching. Loss of ptr-18 caused a significant delay in GRL-7 clearance, causing this protein to be retained in the extracellular space in newly hatched ptr-18 mutant larvae. Furthermore, the putative transporter activity of PTR-18 was shown to be required for the appropriate function of the protein. These findings not only uncover a previously undescribed role of PTR/PTCHD in the clearance of extracellular hedgehog-related proteins via endocytosis-mediated degradation but also illustrate that failure to temporally restrict intercellular signaling during embryogenesis can subsequently compromise post-embryonic progenitor cell function. Inside the animal body, many “signals” are exchanged between tissues and cells to ensure healthy growth and physiological conditions. Too much or less signals have been known to cause various diseases such as cancer and diabetes. When developing animals are not fed enough food, their growth rates generally slow down. We found that when nematodes lacking the PTR-18 protein are hatched out of the egg in the absence of sufficient food, they do not appropriately halt their growth. Analyses at the molecular and cellular levels showed that immediately before hatching, PTR-18 re-uptakes a signaling molecule called GRL-7, which is known to promote growth, from the outside to the inside of cells, resulting in the degradation of GRL-7. As a result, worms lacking PTR-18 still contain excess GRL-7 after hatching, which results in unwanted growth even when ample food is not available. Thus, our findings uncover the role of PTR-18 in terminating a signal on time. Humans also possess a protein called PTCHD1, which is structurally similar to the worm’s PTR-18 and has been proposed to cause autistic spectrum disorders and learning disabilities. Our findings may provide a clue to further understand the function of human PTCHD1.
登录
查看更多内容
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Bidet M;Joubert O;Lacombe B;Ciantar M;Nehmé R;Mollat P;Brétillon L;Faure H;Bittman R;Ruat M;Mus-Veteau I
通讯作者：
Mus-Veteau I
影响因子：
3.3
作者：
Dokshin GA;Ghanta KS;Piscopo KM;Mello CC
通讯作者：
Mello CC
影响因子：
3.5
作者：
Chaudhry, A.;Noor, A.;Carter, M. T.
通讯作者：
Carter, M. T.
影响因子：
9.2
作者：
Fukuyama, M;Rougvie, AE;Rothman, JH
通讯作者：
Rothman, JH