FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation

被引:77
作者
Popow, Johannes [1 ]
Alleaume, Anne-Marie [1 ]
Curk, Tomaz [2 ]
Schwarzl, Thomas [1 ]
Sauer, Sven [3 ]
Hentze, Matthias W. [1 ]
机构
[1] European Mol Biol Lab, D-69117 Heidelberg, Germany
[2] Univ Ljubljana, Fac Comp & Informat Sci, Ljubljana 1000, Slovenia
[3] Univ Childrens Hosp Heidelberg, Dept Gen Pediat, Div Inherited Metab Dis, D-69120 Heidelberg, Germany
基金
欧洲研究理事会;
关键词
RNA-binding proteins; iCLIP; mitochondria; transcript processing; oxidative phosphorylation; Mendelian disease; MESSENGER-RNA; RIBOSOMAL-RNA; TRANSCRIPTION; GRANULES; EXPRESSION; STABILITY; RAP;
D O I
10.1261/rna.052365.115
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mitochondrial RNA processing is an essential step for the synthesis of the components of the electron transport chain in all eukaryotic organisms, yet several aspects of mitochondrial RNA biogenesis and regulation are not sufficiently understood. RNA interactome capture identified several disease-relevant RNA-binding proteins (RBPs) with noncanonical RNA-binding architectures, including all six members of the FASTK (FAS-activated serine/threonine kinase) family of proteins. A mutation within one of these newly assigned FASTK RBPs, FASTKD2, causes a rare form of Mendelian mitochondrial encephalomyopathy. To investigate whether RNA binding of FASTKD2 contributes to the disease phenotype, we identified the RNA targets of FASTKD2 by iCLIP. FASTKD2 interacts with a defined set of mitochondrial transcripts including 16S ribosomal RNA (RNR2) and NADH dehydrogenase subunit 6 (ND6) messenger RNA. CRISPR-mediated deletion of FASTKD2 leads to aberrant processing and expression of RNR2 and ND6 mRNA that encodes a subunit of the respiratory complex I. Metabolic phenotyping of FASTKD2-deficient cells reveals impaired cellular respiration with reduced activities of all respiratory complexes. This work identifies key aspects of the molecular network of a previously uncharacterized, disease-relevant RNA-binding protein, FASTKD2, by a combination of genomic, molecular, and metabolic analyses.
引用
收藏
页码:1873 / 1884
页数:12
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