title: Tysnd1 deficiency in mice interferes with the peroxisomal localization of PTS2 enzymes, causing lipid metabolic abnormalities and male infertility.
abstract: 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.
authors: Division of Functional Genomics and Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors: Yumi
authors: Y
authors: Mizuno
authors: Yuichi
authors: Y
authors: Ninomiya
authors: Yutaka
authors: Y
authors: Nakachi
authors: Mioko
authors: M
authors: Iseki
authors: Hiroyasu
authors: H
authors: Iwasa
authors: Masumi
authors: M
authors: Akita
authors: Tohru
authors: T
authors: Tsukui
authors: Nobuyuki
authors: N
authors: Shimozawa
authors: Chizuru
authors: C
authors: Ito
authors: Kiyotaka
authors: K
authors: Toshimori
authors: Megumi
authors: M
authors: Nishimukai
authors: Hiroshi
authors: H
authors: Hara
authors: Ryouta
authors: R
authors: Maeba
authors: Tomoki
authors: T
authors: Okazaki
authors: Ali Nasser Ali
authors: AN
authors: Alodaib
authors: Mohammed
authors: M
authors: Al Amoudi
authors: Minnie
authors: M
authors: Jacob
authors: Fowzan S
authors: FS
authors: Alkuraya
authors: Yasushi
authors: Y
authors: Horai
authors: Mitsuhiro
authors: M
authors: Watanabe
authors: Hiromi
authors: H
authors: Motegi
authors: Shigeharu
authors: S
authors: Wakana
authors: Tetsuo
authors: T
authors: Noda
authors: Igor V
authors: IV
authors: Kurochkin
authors: Yosuke
authors: Y
authors: Mizuno
authors: Christian
authors: C
authors: Schönbach
authors: Yasushi
authors: Y
authors: Okazaki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D003546:Cysteine Endopeptidases / Q000235:genetics*; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D000074437:Peroxisomal Targeting Signal 2 Receptor; D020675:Peroxisomes / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism
chemical_list: D000074437:Peroxisomal Targeting Signal 2 Receptor; D021382:Protein Sorting Signals; D018160:Receptors, Cytoplasmic and Nuclear; D057057:Serine Proteases; D012697:Serine Endopeptidases; C570301:Tysnd1 protein, human; C581621:Tysnd1 protein, mouse; D003546:Cysteine Endopeptidases