The FASTK Family Proteins Fine-tune Mitochondrial RNA Processing

Overview

Journal PLoS Genet

Specialty Genetics

Date 2021 Nov 8

PMID 34748562

Citations 15

Authors

Akira Ohkubo

Lindsey Van Haute

Danielle L Rudler

Maike Stentenbach

Florian A Steiner

Oliver Rackham

Michal Minczuk

Aleksandra Filipovska

Jean-Claude Martinou

Affiliations

Soon will be listed here.

Abstract

Transcription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the tRNAs that flank most rRNAs and mRNAs. However, some mRNAs are not punctuated by tRNAs, and it remains largely unknown how these non-canonical junctions are resolved. The FASTK family proteins are emerging as key players in non-canonical RNA processing. Here, we have generated human cell lines carrying single or combined knockouts of several FASTK family members to investigate their roles in non-canonical RNA processing. The most striking phenotypes were obtained with loss of FASTKD4 and FASTKD5 and with their combined double knockout. Comprehensive mitochondrial transcriptome analyses of these cell lines revealed a defect in processing at several canonical and non-canonical RNA junctions, accompanied by an increase in specific antisense transcripts. Loss of FASTKD5 led to the most severe phenotype with marked defects in mitochondrial translation of key components of the electron transport chain complexes and in oxidative phosphorylation. We reveal that the FASTK protein family members are crucial regulators of non-canonical junction and non-coding mitochondrial RNA processing.

Citing Articles

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References

Davies S, Sanchez M, Narsai R, Shearwood A, Razif M, Small I . MRPS27 is a pentatricopeptide repeat domain protein required for the translation of mitochondrially encoded proteins. FEBS Lett. 2012; 586(20):3555-61. DOI: 10.1016/j.febslet.2012.07.043. View

Zangari J, Petrelli F, Maillot B, Martinou J . The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier. Biomolecules. 2020; 10(7). PMC: 7407832. DOI: 10.3390/biom10071068. View

Jourdain A, Koppen M, Wydro M, Rodley C, Lightowlers R, Chrzanowska-Lightowlers Z . GRSF1 regulates RNA processing in mitochondrial RNA granules. Cell Metab. 2013; 17(3):399-410. PMC: 3593211. DOI: 10.1016/j.cmet.2013.02.005. View

Rivier C, Goldschmidt-Clermont M, Rochaix J . Identification of an RNA-protein complex involved in chloroplast group II intron trans-splicing in Chlamydomonas reinhardtii. EMBO J. 2001; 20(7):1765-73. PMC: 145512. DOI: 10.1093/emboj/20.7.1765. View

Izquierdo J, Valcarcel J . Fas-activated serine/threonine kinase (FAST K) synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing. J Biol Chem. 2006; 282(3):1539-43. DOI: 10.1074/jbc.C600198200. View

Back J, Sanz M, de Jong L, de Koning L, Nijtmans L, de Koster C . A structure for the yeast prohibitin complex: Structure prediction and evidence from chemical crosslinking and mass spectrometry. Protein Sci. 2002; 11(10):2471-8. PMC: 2373692. DOI: 10.1110/ps.0212602. View

Xu F, Ackerley C, Maj M, Addis J, Levandovskiy V, Lee J . Disruption of a mitochondrial RNA-binding protein gene results in decreased cytochrome b expression and a marked reduction in ubiquinol-cytochrome c reductase activity in mouse heart mitochondria. Biochem J. 2008; 416(1):15-26. DOI: 10.1042/BJ20080847. View

Gustafsson C, Falkenberg M, Larsson N . Maintenance and Expression of Mammalian Mitochondrial DNA. Annu Rev Biochem. 2016; 85:133-60. DOI: 10.1146/annurev-biochem-060815-014402. View

DSouza A, Minczuk M . Mitochondrial transcription and translation: overview. Essays Biochem. 2018; 62(3):309-320. PMC: 6056719. DOI: 10.1042/EBC20170102. View

10.

Van Nostrand E, Freese P, Pratt G, Wang X, Wei X, Xiao R . A large-scale binding and functional map of human RNA-binding proteins. Nature. 2020; 583(7818):711-719. PMC: 7410833. DOI: 10.1038/s41586-020-2077-3. View

11.

Sakuma T, Nishikawa A, Kume S, Chayama K, Yamamoto T . Multiplex genome engineering in human cells using all-in-one CRISPR/Cas9 vector system. Sci Rep. 2014; 4:5400. PMC: 4066266. DOI: 10.1038/srep05400. View

12.

Steczkiewicz K, Muszewska A, Knizewski L, Rychlewski L, Ginalski K . Sequence, structure and functional diversity of PD-(D/E)XK phosphodiesterase superfamily. Nucleic Acids Res. 2012; 40(15):7016-45. PMC: 3424549. DOI: 10.1093/nar/gks382. View

13.

Glanz S, Kuck U . Trans-splicing of organelle introns--a detour to continuous RNAs. Bioessays. 2009; 31(9):921-34. DOI: 10.1002/bies.200900036. View

14.

Borowski L, Dziembowski A, Hejnowicz M, Stepien P, Szczesny R . Human mitochondrial RNA decay mediated by PNPase-hSuv3 complex takes place in distinct foci. Nucleic Acids Res. 2012; 41(2):1223-40. PMC: 3553951. DOI: 10.1093/nar/gks1130. View

15.

Gaur R, Grasso D, Datta P, Krishna P, Das G, Spencer A . A single mammalian mitochondrial translation initiation factor functionally replaces two bacterial factors. Mol Cell. 2008; 29(2):180-90. PMC: 2605297. DOI: 10.1016/j.molcel.2007.11.021. View

16.

Hallberg B, Larsson N . Making proteins in the powerhouse. Cell Metab. 2014; 20(2):226-40. DOI: 10.1016/j.cmet.2014.07.001. View

17.

Pearce S, Rebelo-Guiomar P, DSouza A, Powell C, Van Haute L, Minczuk M . Regulation of Mammalian Mitochondrial Gene Expression: Recent Advances. Trends Biochem Sci. 2017; 42(8):625-639. PMC: 5538620. DOI: 10.1016/j.tibs.2017.02.003. View

18.

Ojala D, Montoya J, Attardi G . tRNA punctuation model of RNA processing in human mitochondria. Nature. 1981; 290(5806):470-4. DOI: 10.1038/290470a0. View

19.

Brzezniak L, Bijata M, Szczesny R, Stepien P . Involvement of human ELAC2 gene product in 3' end processing of mitochondrial tRNAs. RNA Biol. 2011; 8(4):616-26. DOI: 10.4161/rna.8.4.15393. View

20.

Jourdain A, Popow J, de la Fuente M, Martinou J, Anderson P, Simarro M . The FASTK family of proteins: emerging regulators of mitochondrial RNA biology. Nucleic Acids Res. 2017; 45(19):10941-10947. PMC: 5737537. DOI: 10.1093/nar/gkx772. View