担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Biochemistry  

Protein targeting to organelles has been thought to be a very precise process, and proteins that fail to localize correctly are rapidly degraded. Tail-anchored proteins are posttranslationally targeted to the endoplasmic reticulum membrane via guided entry of tail-anchored (TA) proteins pathway. However, these proteins can be mislocalized to the mitochondrial outer membrane. We found that the AAA-ATPase Msp1 on the mitochondrial outer membrane extracts mislocalized TA proteins to the cytosol, passing them to the guided entry of the TA proteins pathway to facilitate their transfer to the endoplasmic reticulum membrane. After the transfer to the endoplasmic reticulum, such TA proteins are directed to degradation if they are recognized by the quality control system on the endoplasmic reticulum. If not recognized, they are retargeted to their original destination along the secretory pathway. Thus, we have identified an intracellular proofreading system that corrects the localization of TA proteins.

DOI： 10.1093/jb/mvad025

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Science Advances  

Deficiencies in mitochondrial protein import are associated with a number of diseases. However, although nonimported mitochondrial proteins are at great risk of aggregation, it remains largely unclear how their accumulation causes cell dysfunction. Here, we show that nonimported citrate synthase is targeted for proteasomal degradation by the ubiquitin ligase SCFUcc1. Unexpectedly, our structural and genetic analyses revealed that nonimported citrate synthase appears to form an enzymatically active conformation in the cytosol. Its excess accumulation caused ectopic citrate synthesis, which, in turn, led to an imbalance in carbon flux of sugar, a reduction of the pool of amino acids and nucleotides, and a growth defect. Under these conditions, translation repression is induced and acts as a protective mechanism that mitigates the growth defect. We propose that the consequence of mitochondrial import failure is not limited to proteotoxic insults, but that the accumulation of a nonimported metabolic enzyme elicits ectopic metabolic stress.

DOI： 10.1126/sciadv.adf1956

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出版者・発行元：Journal of Biochemistry  

Normal cellular functions rely on correct protein localization within cells. Protein targeting had been thought to be a precise process, and even if it fails, the mistargeted proteins were supposed to be quickly degraded. However, this view is rapidly changing. Tail-anchored (TA) proteins are a class of membrane proteins that possess a single transmembrane domain (TMD) near the C-terminus and are posttranslationally targeted to the endoplasmic reticulum (ER) membrane, mitochondrial outer membrane (OM), and peroxisomal membrane, yet they can be mistargeted to the mitochondrial OM. The mistargeted TA proteins can be extracted from the OM by a mitochondrial AAA-ATPase Msp1/ATAD1 and transferred to the ER. If they are regarded as aberrant by the ER protein quality control system, they are extracted from the ER membrane for proteasomal degradation in the cytosol. If they are not regarded as aberrant, they are further transported to downstream organelles or original destinations along the secretory pathway. Thus, Msp1 contributes to not only degradation but also "proofreading"of the targeting of mislocalized TA proteins.

DOI： 10.1093/jb/mvac097

Scopus

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1126/sciadv.adf1956.

DOI： 10.1093/jb/mvac097

Web of Science

PubMed

記述言語：英語  

DOI： 10.1093/jb/mvac097

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Normal cellular functions rely on correct protein localization within cells. Protein targeting had been thought to be a precise process, and even if it fails, the mistargeted proteins were supposed to be quickly degraded. However, this view is rapidly changing. Tail-anchored (TA) proteins are a class of membrane proteins that possess a single transmembrane domain (TMD) near the C-terminus and are posttranslationally targeted to the endoplasmic reticulum (ER) membrane, mitochondrial outer membrane (OM), and peroxisomal membrane, yet they can be mistargeted to the mitochondrial OM. The mistargeted TA proteins can be extracted from the OM by a mitochondrial AAA-ATPase Msp1/ATAD1 and transferred to the ER. If they are regarded as aberrant by the ER protein quality control system, they are extracted from the ER membrane for proteasomal degradation in the cytosol. If they are not regarded as aberrant, they are further transported to downstream organelles or original destinations along the secretory pathway. Thus, Msp1 contributes to not only degradation but also "proofreading" of the targeting of mislocalized TA proteins.

DOI： 10.1093/jb/mvac097

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記述言語：日本語   出版者・発行元：公益社団法人日本生化学会  

真核生物の細胞内では合成されたタンパク質が，目的の細胞小器官（オルガネラ）に配送されることは正常な細胞機能に必要である．従来タンパク質の配送は非常に正確なプロセスであり，異なる配送先に誤って局在したタンパク質は，細胞の品質管理機構により速やかに分解されると考えられてきた．しかし，現在この考え方が大きく変わりつつある．C末端に膜貫通配列（TMD）を一つ持つテイルアンカー型（TA）膜タンパク質は，小胞体（ER）膜，ミトコンドリア外膜そしてペルオキシソーム膜に配送されるが，オルガネラへのタンパク質配送経路の変異などによりミトコンドリア外膜に誤配送されることがある．筆者らは，ミトコンドリア外膜に局在するAAA-ATPアーゼMsp1（酵母）/ATAD1（哺乳動物）が誤配送TAタンパク質を膜から引き抜くことで，分解だけでなく，配送のやり直し（校正）に関わることを見いだし，分子機構を明らかにしてきた．本稿では，「TAタンパク質のオルガネラ局在化における配送校正機構」について概説する．

DOI： 10.14952/seikagaku.2023.950017

Scopus

CiNii Research

記述言語：日本語   出版者・発行元：公益社団法人 日本農芸化学会  

DOI： 10.1271/kagakutoseibutsu.60.496

CiNii Research

CiNii Research

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-38016-1

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.carres.2015.05.010

開催年月日： 2018年11月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

開催年月日： 2018年6月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

記述言語：日本語  

会議種別：口頭発表（招待・特別）  

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記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：口頭発表（招待・特別）  

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記述言語：日本語  

記述言語：日本語  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：英語   出版者・発行元：(公社)日本生化学会  

記述言語：英語   出版者・発行元：(公社)日本生化学会  

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

真核生物の細胞内では合成されたタンパク質が,目的の細胞小器官(オルガネラ)に配送されることは正常な細胞機能に必要である.従来タンパク質の配送は非常に正確なプロセスであり,異なる配送先に誤って局在したタンパク質は,細胞の品質管理機構により速やかに分解されると考えられてきた.しかし,現在この考え方が大きく変わりつつある.C末端に膜貫通配列(TMD)を一つ持つテイルアンカー型(TA)膜タンパク質は,小胞体(ER)膜,ミトコンドリア外膜そしてペルオキシソーム膜に配送されるが,オルガネラへのタンパク質配送経路の変異などによりミトコンドリア外膜に誤配送されることがある.筆者らは,ミトコンドリア外膜に局在するAAA-ATPアーゼMsp1(酵母)/ATAD1(哺乳動物)が誤配送TAタンパク質を膜から引き抜くことで,分解だけでなく,配送のやり直し(校正)に関わることを見いだし,分子機構を明らかにしてきた.本稿では,「TAタンパク質のオルガネラ局在化における配送校正機構」について概説する.(著者抄録)

記述言語：日本語   出版者・発行元：(公社)日本農芸化学会  

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掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

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J-GLOBAL

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