Tysnd1 deficiency in mice interferes with the peroxisomal localization of PTS2 enzymes, causing lipid metabolic abnormalities and male infertility.
Tysnd1 deficiency in mice interferes with the peroxisomal localization of PTS2 enzymes, causing lipid metabolic abnormalities and male infertility.
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DOI：
10.1371/journal.pgen.1003286
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Okazaki Y
中科院分区：
文献类型：
--
作者：
Mizuno Y;Ninomiya Y;Nakachi Y;Iseki M;Iwasa H;Akita M;Tsukui T;Shimozawa N;Ito C;Toshimori K;Nishimukai M;Hara H;Maeba R;Okazaki T;Alodaib AN;Al Amoudi M;Jacob M;Alkuraya FS;Horai Y;Watanabe M;Motegi H;Wakana S;Noda T;Kurochkin IV;Mizuno Y;Schönbach C;Okazaki Y
过氧化物酶体是参与脂质代谢过程的亚细胞器，包括极长链脂肪酸和支链脂肪酸等。过氧化物酶体基质蛋白在细胞质中合成。过氧化物酶体基质蛋白C-末端（PTS 1）或N-末端（PTS 2）的靶向信号（PTS或过氧化物酶体靶向信号）介导其输入细胞器。在含有PTS 2的蛋白质的情况下，当运输到过氧化物酶体中时，PTS 2信号从蛋白质中切割。然而，PTS 2加工的功能机制知之甚少。以前，我们确定了Tysnd 1（胰蛋白酶域1）和生化特性，它作为一个过氧化物酶体半胱氨酸内肽酶，直接处理含PTS 2的prethiolase α 1和含PTS 1的Acox 1，Hsd 17 b4和ScpX。后三种酶是极长链脂肪酸β-氧化途径的重要组成部分。为了阐明Tysnd 1的体内功能和生理作用，我们分析了Tysnd 1 −/−小鼠的表型。雄性Tysnd 1 −/−小鼠不育，附睾精子缺乏顶体帽。这些表型特征最有可能是胆碱和乙醇胺缩醛磷脂分子种类组成变化的结果。Tysnd 1 −/−小鼠在口服植烷酸前体植醇时也出现肝功能障碍。Phyh和Agps是已知的含有PTS 2的蛋白质，但被鉴定为新的Tysnd 1底物。Tysnd 1基因的缺失干扰了Tysa 1、Phyh和Agps的过氧化物酶体定位，这可能导致轻度Zellweger综合征谱样表型。我们的数据表明，过氧化物酶体加工蛋白酶Tysnd 1是必要的，以介导的生理功能的PTS 2含有基板。过氧化物酶体是存在于几乎所有真核细胞中的亚细胞器。音节“per-oxi”反映了这些单膜结合细胞器在各种代谢过程中的氧化功能，包括极长链脂肪酸和支链脂肪酸。在早期的研究中，我们发现了一种名为Tysnd 1的蛋白酶，它特异性地位于过氧化物酶体中，并加工催化极长链脂肪酸的过氧化物酶体β-氧化的酶。在这项研究中，我们确定了两个新的Tysnd 1底物，Agps和Phyh，这是参与缩醛磷脂合成和植烷酸代谢，分别。为了进一步研究Tysnd 1的体内功能，我们分析了Tysnd 1敲除小鼠。缺乏Tysnd 1的小鼠表现出过氧化物酶体β-氧化活性降低和缩醛原组成改变，以及植烷酸代谢异常。男性不育是Tysnd 1缺陷的主要表型表现之一。我们的数据支持Tysnd 1影响过氧化物酶体内某些底物的定位和活性的观点。总之，我们的Tysnd 1缺陷小鼠模型扩展了目前过氧化物酶体生物学知识的分子致病机制，可能与一些患者Zellweger综合征谱系障碍。
Peroxisomes are subcellular organelles involved in lipid metabolic processes, including those of very-long-chain fatty acids and branched-chain fatty acids, among others. Peroxisome matrix proteins are synthesized in the cytoplasm. Targeting signals (PTS or peroxisomal targeting signal) at the C-terminus (PTS1) or N-terminus (PTS2) of peroxisomal matrix proteins mediate their import into the organelle. In the case of PTS2-containing proteins, the PTS2 signal is cleaved from the protein when transported into peroxisomes. The functional mechanism of PTS2 processing, however, is poorly understood. Previously we identified Tysnd1 (Trypsin domain containing 1) and biochemically characterized it as a peroxisomal cysteine endopeptidase that directly processes PTS2-containing prethiolase Acaa1 and PTS1-containing Acox1, Hsd17b4, and ScpX. The latter three enzymes are crucial components of the very-long-chain fatty acids β-oxidation pathway. To clarify the in vivo functions and physiological role of Tysnd1, we analyzed the phenotype of Tysnd1−/− mice. Male Tysnd1−/− mice are infertile, and the epididymal sperms lack the acrosomal cap. These phenotypic features are most likely the result of changes in the molecular species composition of choline and ethanolamine plasmalogens. Tysnd1−/− mice also developed liver dysfunctions when the phytanic acid precursor phytol was orally administered. Phyh and Agps are known PTS2-containing proteins, but were identified as novel Tysnd1 substrates. Loss of Tysnd1 interferes with the peroxisomal localization of Acaa1, Phyh, and Agps, which might cause the mild Zellweger syndrome spectrum-resembling phenotypes. Our data established that peroxisomal processing protease Tysnd1 is necessary to mediate the physiological functions of PTS2-containing substrates. Peroxisomes are subcellular organelles that are present in almost all eukaryotic cells. The syllables “per-oxi” reflect the oxidative functions of these single-membrane-bound organelles in various metabolic processes, including those of very-long-chain fatty acids and branched-chain fatty acids. In an earlier study we identified a protease named Tysnd1 that is specifically located in the peroxisomes and processes the enzymes catalyzing the peroxisomal β-oxidation of very-long-chain fatty acids. In this study, we identified two novel Tysnd1 substrates, Agps and Phyh, which are involved in plasmalogen synthesis and phytanic acid metabolism, respectively. To further investigate the in vivo function of Tysnd1, we analyzed Tysnd1 knock-out mice. Mice that lack Tysnd1 showed reduced peroxisomal β-oxidation activity and an altered plasmalogen composition, as well as an abnormal phytanic acid metabolism. Male infertility is one of the major phenotypic manifestations of Tysnd1 deficiency. Our data support the idea that Tysnd1 affects the localization and activity of some of its substrates inside peroxisomes. Altogether, our Tysnd1-deficient mouse model expands the current peroxisome biology knowledge with regard to the molecular pathogenic mechanisms that may be relevant to some patients with Zellweger syndrome spectrum disorders.
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影响因子：
1.5
作者：
Mackie, John T.;Atshaves, Barbara P.;Kier, Ann B.
通讯作者：
Kier, Ann B.
影响因子：
4.8
作者：
de Vet, ECJM;Ijlst, L;van den Bosch, H
通讯作者：
van den Bosch, H
影响因子：
3.5
作者：
Braverman, N;Dodt, G;Valle, D
通讯作者：
Valle, D
影响因子：
4.8
作者：
Erol, Erdal;Kumar, Leena S.;Binas, Bert
通讯作者：
Binas, Bert
DOI：
10.1073/pnas.0806066105
发表时间：
2008-11-18
影响因子：
11.1
作者：
Ferdinandusse, Sacha;Zomer, Anna W. M.;Brites, Pedro
通讯作者：
Brites, Pedro