Human Mitochondrial SUV3 and Polynucleotide Phosphorylase Form a 330-kDa Heteropentamer to Cooperatively Degrade Double-stranded RNA with a 3′-to-5′ Directionality

Results strongly suggest that the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA and may be the long sought RNA-degrading complex in the mammalian mitochondria.

Abstract

Efficient turnover of unnecessary and misfolded RNAs is critical for maintaining the integrity and function of the mitochondria. The mitochondrial RNA degradosome of budding yeast (mtEXO) has been recently studied and characterized; yet no RNA degradation machinery has been identified in the mammalian mitochondria. In this communication, we demonstrated that purified human SUV3 (suppressor of Var1 3) dimer and polynucleotide phosphorylase (PNPase) trimer form a 330-kDa heteropentamer that is capable of efficiently degrading double-stranded RNA (dsRNA) substrates in the presence of ATP, a task the individual components cannot perform separately. The configuration of this complex is similar to that of the core complex of the E. coli RNA degradosome lacking RNase E but very different from that of the yeast mtEXO. The hSUV3-hPNPase complex prefers substrates containing a 3′ overhang and degrades the RNA in a 3′-to-5′ directionality. Deleting a short stretch of amino acids (positions 510–514) compromises the ability of hSUV3 to form a stable complex with hPNPase to degrade dsRNA substrates but does not affect its helicase activity. Furthermore, two additional hSUV3 mutants with abolished helicase activity because of disrupted ATPase or RNA binding activities were able to bind hPNPase. However, the resulting complexes failed to degrade dsRNA, suggesting that an intact helicase activity is essential for the complex to serve as an effective RNA degradosome. Taken together, these results strongly suggest that the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA and may be the long sought RNA-degrading complex in the mammalian mitochondria. Efficient turnover of unnecessary and misfolded RNAs is critical for maintaining the integrity and function of the mitochondria. The mitochondrial RNA degradosome of budding yeast (mtEXO) has been recently studied and characterized; yet no RNA degradation machinery has been identified in the mammalian mitochondria. In this communication, we demonstrated that purified human SUV3 (suppressor of Var1 3) dimer and polynucleotide phosphorylase (PNPase) trimer form a 330-kDa heteropentamer that is capable of efficiently degrading double-stranded RNA (dsRNA) substrates in the presence of ATP, a task the individual components cannot perform separately. The configuration of this complex is similar to that of the core complex of the E. coli RNA degradosome lacking RNase E but very different from that of the yeast mtEXO. The hSUV3-hPNPase complex prefers substrates containing a 3′ overhang and degrades the RNA in a 3′-to-5′ directionality. Deleting a short stretch of amino acids (positions 510–514) compromises the ability of hSUV3 to form a stable complex with hPNPase to degrade dsRNA substrates but does not affect its helicase activity. Furthermore, two additional hSUV3 mutants with abolished helicase activity because of disrupted ATPase or RNA binding activities were able to bind hPNPase. However, the resulting complexes failed to degrade dsRNA, suggesting that an intact helicase activity is essential for the complex to serve as an effective RNA degradosome. Taken together, these results strongly suggest that the complex of hSUV3-hPNPase is an integral entity for efficient degradation of structured RNA and may be the long sought RNA-degrading complex in the mammalian mitochondria. The current opinion on mitochondrial RNA degradation is largely based on our understanding of the Escherichia coli RNA degradosome and the yeast mitochondrial degradosome (mtEXO). The E. coli RNA degradosome consists of four components: RNase E, an endoribonuclease in which the C terminus serves as the scaffold of the multiprotein complex; PNPase, 4The abbreviations used are: PNPasepolynucleotide phosphorylasedsRNAdouble-stranded RNAssRNAsingle-stranded RNAhhumanGSTglutathione S-transferaseWTwild typeRNAiRNA interferenceOHoverhang. an ambivalent enzyme that catalyzes 3′-to-5′ phosphorolysis as well as 5′-to-3′ polymerization of RNA; RhlB, a DEAD-box helicase; and enolase, a glycolytic enzyme (1Grunberg-Manago M. Annu. Rev. Genet. 1999; 33: 193-227Crossref PubMed Scopus (243) Google Scholar, 2Carpousis A.J. Van Houwe G. Ehretsmann C. Krisch H.M. Cell. 1994; 76: 889-900Abstract Full Text PDF PubMed Scopus (385) Google Scholar, 3Py B. Causton H. Mudd E.A. Higgins C.F. Mol. Microbiol. 1994; 14: 717-729Crossref PubMed Scopus (203) Google Scholar, 4Carpousis A.J. Annu. Rev. Microbiol. 2007; 61: 71-87Crossref PubMed Scopus (368) Google Scholar, 5Py B. Higgins C.F. Krisch H.M. Carpousis A.J. Nature. 1996; 381: 169-172Crossref PubMed Scopus (478) Google Scholar, 6Miczak A. Kaberdin V.R. Wei C.L. Lin-Chao S. Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 3865-3869Crossref PubMed Scopus (316) Google Scholar, 7Mohanty B.K. Kushner S.R. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 11966-11971Crossref PubMed Scopus (218) Google Scholar). The 4-MDa multi-enzyme complex has been postulated to have a molar ratio of 4 RNase E:12 PNPase:4 RhlB:8 enolase (2Carpousis A.J. Van Houwe G. Ehretsmann C. Krisch H.M. Cell. 1994; 76: 889-900Abstract Full Text PDF PubMed Scopus (385) Google Scholar, 4Carpousis A.J. Annu. Rev. Microbiol. 2007; 61: 71-87Crossref PubMed Scopus (368) Google Scholar, 5Py B. Higgins C.F. Krisch H.M. Carpousis A.J. Nature. 1996; 381: 169-172Crossref PubMed Scopus (478) Google Scholar, 8Blum E. Py B. Carpousis A.J. Higgins C.F. Mol. Microbiol. 1997; 26: 387-398Crossref PubMed Scopus (112) Google Scholar, 9Ehretsmann C.P. Carpousis A.J. Krisch H.M. Genes Dev. 1992; 6: 149-159Crossref PubMed Scopus (184) Google Scholar, 10Callaghan A.J. Marcaida M.J. Stead J.A. McDowall K.J. Scott W.G. Luisi B.F. Nature. 2005; 437: 1187-1191Crossref PubMed Scopus (226) Google Scholar). More recently, it has been reported that in the absence of RNase E, RhlB and PNPase can form a 380-kDa complex (2 RhlB:3 PNPase) to degrade dsRNA substrates (11Liou G.G. Chang H.Y. Lin C.S. Lin-Chao S. J. Biol. Chem. 2002; 277: 41157-41162Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 12Lin P.H. Lin-Chao S. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 16590-16595Crossref PubMed Scopus (56) Google Scholar, 13Lin-Chao S. Chiou N.T. Schuster G. J. Biomed. Sci. 2007; 14: 523-532Crossref PubMed Scopus (57) Google Scholar). In budding yeast, an ATP-dependent DExH/D-box RNA helicase, Suv3p, and a 3′-to-5′ directed exoribonuclease, Dss1, have been demonstrated to be the essential components of the mtEXO (14Dziembowski A. Piwowarski J. Hoser R. Minczuk M. Dmochowska A. Siep M. van der Spek H. Grivell L. Stepien P.P. J. Biol. Chem. 2003; 278: 1603-1611Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). In vitro, the two proteins have been shown to form a heterodimer that is capable of degrading dsRNA substrates containing a 3′ overhang (15Malecki M. Jedrzejczak R. Stepien P.P. Golik P. J. Mol. Biol. 2007; 372: 23-36Crossref PubMed Scopus (43) Google Scholar). Unlike its counterpart in the E. coli RNA degradosome, Dss1 does not form a trimeric ring structure but belongs to the RNR family of exoribonucleases that are mainly involved in rRNA maturation in the chloroplast of higher plants (16Dziembowski A. Malewicz M. Minczuk M. Golik P. Dmochowska A. Stepien P.P. Mol. Gen. Genet. 1998; 260: 108-114Crossref PubMed Scopus (63) Google Scholar). polynucleotide phosphorylase double-stranded RNA single-stranded RNA human glutathione S-transferase wild type RNA interference overhang. In these well studied systems, the RNA-degrading complexes always contain an ATP-dependent RNA helicase to unwind the secondary structures of the RNA, followed by 3′-5′ degradation by an exoribonuclease. This provides a fundamental concept in RNA degradation; once a RNA molecule has been identified and marked for elimination, possibly mediated by 3′ polyadenylation (17Slomovic S. Portnoy V. Yehudai-Resheff S. Bronshtein E. Schuster G. Biochim. Biophys. Acta. 2008; 1779: 247-255Crossref PubMed Scopus (52) Google Scholar, 18Slomovic S. Laufer D. Geiger D. Schuster G. Mol. Cell Biol. 2005; 25: 6427-6435Crossref PubMed Scopus (134) Google Scholar), a coordinated process involving secondary structure removal and exoribonucleolytic trimming must take place simultaneously for efficient RNA removal. Currently, no RNA-degrading complex has been identified in the mammalian mitochondria, mainly because the key components of the E. coli RNA degradosome and the yeast mtEXO do not appear to be evolutionarily conserved. Nevertheless, to maintain its proper function and integrity, the mammalian mitochondria need a mechanism to efficiently remove unnecessary and/or misfolded RNA transcripts. In the search for the RNA-degrading complex in the human mitochondria, the human homologues of the key components of the E. coli RNA degradosome and the yeast mtEXO were examined. It that SUV3 and PNPase not have human homologues but contain an mitochondrial and in the mitochondria J. P. A. Dmochowska A. Minczuk M. Stepien P.P. J. Mol. Biol. 2003; PubMed Scopus Google Scholar, M. Piwowarski J. S. A. Dmochowska A. E. Stepien P.P. P. 2002; PubMed Scopus Google Scholar). reported that purified human SUV3 an ATP-dependent helicase activity for dsRNA, and S. C.F. PubMed Scopus Google Scholar). PNPase shown to form a ring trimer structure similar to its in E. coli and chloroplast and the S. Laufer D. Geiger D. Schuster G. Mol. Cell Biol. 2005; 25: 6427-6435Crossref PubMed Scopus (134) Google Scholar, V. G. Yehudai-Resheff S. Schuster G. 2008; 14: PubMed Scopus Google Scholar, D. PubMed Scopus Google Scholar, E. Carpousis A.J. Higgins C.F. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. Schuster G. Mol. Cell Biol. PubMed Scopus Google Scholar, S. Portnoy V. S. Schuster G. Cell. 2003; PubMed Scopus Google and RNA and activities in S. Laufer D. Geiger D. Schuster G. Mol. Cell Biol. 2005; 25: 6427-6435Crossref PubMed Scopus (134) Google Scholar, V. G. Yehudai-Resheff S. Schuster G. 2008; 14: PubMed Scopus Google Scholar). However, these two in the mammalian mitochondria to be In this we demonstrated that the purified hSUV3 a complex with hPNPase a molar The resulting 330-kDa complex efficiently degrades containing 3′ overhang in an ATP-dependent a task the individual components cannot perform separately. binding and a short stretch acids 510–514) of hSUV3 to be critical for hPNPase Deleting these amino acids compromises the ability of hSUV3 to with hPNPase to degrade Furthermore, two hSUV3 and that ATPase and were able to form stable complexes with hPNPase. However, the resulting complexes were to degrade these results suggest that the complex by hSUV3 and hPNPase is an integral entity for efficient degradation of structured SUV3 by the amino acids and with by the as a The The a and a of The hSUV3 and mutants in this and were by as a PNPase the as SUV3 and The a and a of proteins were in a for 4 in of in M. L. in Scholar). The were in with proper a an of the with for the were 4 The in of containing and by and The were by for with a The by for of to the and on a for The by containing and of and by the purified by with followed by containing purified proteins were in and in hSUV3 and hPNPase proteins were molar and by to the The in of and on a 4 The to remove and by of the were in and in The substrates were from (15Malecki M. Jedrzejczak R. Stepien P.P. Golik P. J. Mol. Biol. 2007; 372: 23-36Crossref PubMed Scopus (43) Google Scholar). The with by polynucleotide purified by with the or to the and helicase are as and of the and used in this were from from by S. C.F. PubMed Scopus Google Scholar). of purified were in helicase and containing of helicase and of The and were and The by an of and The were by The were which and a were based on by S. C.F. PubMed Scopus Google Scholar). RNA of with by polynucleotide and purified by to the helicase with of purified RNA degradation in ATP, containing of short The by of the were a containing and which and the as in the helicase The and the were with by polynucleotide purified by with the of to the and dsRNA RNA degradation in ATP, containing of dsRNA The by an of The were and the as in the helicase The were with a with an hSUV3 hPNPase and a complex from were in the and as a function of were for the proteins and for the The were the and the used to the and of proteins based on amino were from C.F. S. J. 1999; PubMed Scopus Google Scholar). were from G.G. Chang H.Y. Lin C.S. Lin-Chao S. J. Biol. Chem. 2002; 277: 41157-41162Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). the hSUV3-hPNPase were in by a hPNPase on a The were with a of of purified hSUV3 and were in The binding were by the with of of a of the In the E. coli RNA degradosome, RhlB and PNPase form a stable complex a molar ratio (11Liou G.G. Chang H.Y. Lin C.S. Lin-Chao S. J. Biol. Chem. 2002; 277: 41157-41162Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 12Lin P.H. Lin-Chao S. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 16590-16595Crossref PubMed Scopus (56) Google Scholar, 13Lin-Chao S. Chiou N.T. Schuster G. J. Biomed. Sci. 2007; 14: 523-532Crossref PubMed Scopus (57) Google Scholar), in budding yeast, the mitochondrial RNA degradosome is a heterodimer of molecule of and Dss1 (15Malecki M. Jedrzejczak R. Stepien P.P. Golik P. J. Mol. Biol. 2007; 372: 23-36Crossref PubMed Scopus (43) Google Scholar). human SUV3 and PNPase form a complex E. coli or yeast the two proteins were purified to shown in based on the by hSUV3 and hPNPase as a dimer and a hSUV3 and hPNPase ratio the to be a with a of with the individual the complex to and to hSUV3 but hPNPase followed by with and that the complex hSUV3 and hPNPase E and the of the the purified proteins were to by The of hSUV3 and hPNPase were to be and with the of the The of the complex to be which is to that of hSUV3 and hPNPase these results suggest that hSUV3 and hPNPase form a 330-kDa heteropentamer a molar the of this enzyme the activities of the hSUV3-hPNPase complex were with the individual components the substrates shown in molar of the in the presence of hPNPase and the complex to degrade short substrates a similar with the degradation of the that hPNPase is a 3′-5′ and degradation the RNA is long B. Causton H. Mudd E.A. Higgins C.F. Mol. Microbiol. 1994; 14: 717-729Crossref PubMed Scopus (203) Google Scholar, 5Py B. Higgins C.F. Krisch H.M. Carpousis A.J. Nature. 1996; 381: 169-172Crossref PubMed Scopus (478) Google Scholar, Luisi B.F. Carpousis A.J. Sci. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). to in the absence of and in the presence of ATP, the complex to have helicase activity of the helicase activity of hSUV3 that it has a 3′-to-5′ and prefers substrates with a 3′ overhang substrates containing a overhang or a which is with the with purified yeast (15Malecki M. Jedrzejczak R. Stepien P.P. Golik P. J. Mol. Biol. 2007; 372: 23-36Crossref PubMed Scopus (43) Google C and a dsRNA containing an 3′ overhang used to RNAs containing a stable the complex the efficiently hPNPase in an ATP-dependent E and because hSUV3 and hPNPase have a 3′-to-5′ it is no that the complex prefers to degrade dsRNA substrates containing a 3′ overhang to with a overhang results strongly suggest that the hSUV3-hPNPase complex is critical for degrading the structured RNA, a task the individual components cannot that the complex these two is critical for its we a of hSUV3 mutants with the to a that is for hPNPase but not for the helicase activity. we four proteins containing different of the hSUV3 helicase purified hPNPase with the proteins in the binding we that and bind to the does not suggesting that the of hSUV3 is to be the and the of hSUV3 that is for with additional with different of from hSUV3 were mutants were as and shown in the is critical for hPNPase because of the hPNPase of the hPNPase hPNPase by suggesting that a critical binding is However, the is amino the need to the essential for hPNPase on the that the hSUV3-hPNPase complex is critical for the function of the binding for hPNPase must be conserved. we the amino of SUV3 different to search for the not short of amino acids that are and mutants with in these as and the the and mutants binding for hPNPase the in and affect the helicase activity of the mutants were to the helicase helicase activity to the wild type hSUV3 the helicase activity can form a stable complex with the to the complex and hPNPase are a a higher does a higher of the in the suggesting that the the complex this the hPNPase and hSUV3 and were in by a hPNPase on the and the hSUV3 as the of hSUV3 and were to be and and the of binding for of hSUV3 suggesting that the compromises the binding of hSUV3 for hPNPase. these results that we have identified a in hSUV3 that is critical for hPNPase binding but not the helicase activity. the and hPNPase to dsRNA degradation activity in with the wild type shown in the effective in degrading the dsRNA to the wild type suggesting that a stable complex hSUV3 and hPNPase is critical for efficient dsRNA we have that hSUV3 and hPNPase form a complex that degrades dsRNA the of hSUV3 to this process we the helicase activity of hSUV3 serves as an integral of this it demonstrated that a to in the the ATPase and helicase activity of hSUV3 J. P. PubMed Scopus Google Scholar). by the this has a with that of hSUV3 suggesting that the does not the binding of hSUV3 to hPNPase. the complex the as in the complex in which a with a of and hPNPase a ratio However, this complex for the helicase that the complex has helicase activity to the wild type hSUV3-hPNPase complex Furthermore, the complex the dsRNA efficiently to the wild type complex results the of the helicase activity as an integral of the hSUV3-hPNPase complex to efficiently degrade It that an intact helicase of hSUV3 is to dsRNA degradation by the However, the of hSUV3 a in this coordinated activity is not the which failed to bind helicase activity. it that may be in the 510–514) and a essential for the helicase activity. is of the we for a of we a the with these amino acids a of helicase activity the that this may be involved in RNA we an RNA binding and that has a RNA the wild type hSUV3 In the ATPase activity of the failed to its ATPase activity This of serves as to suggest that the is for RNA the complex the as in in which a with a of and hPNPase a ratio with the to bind RNA, the complex has a dsRNA degrading activity to the wild type hSUV3-hPNPase complex these results that is a the C terminus of the helicase that is for RNA binding and the helicase activity of Furthermore, the RNA binding activity of hSUV3 is critical for the dsRNA degradation activity of the suggesting that in to hSUV3 is in of RNA in the In this we demonstrated that hSUV3 and hPNPase form a 330-kDa complex a molar that the helicase and activities of the individual components in a coordinated to degrade dsRNA substrates in the presence of the complex an form of the RNA-degrading complex in the E. coli which the RhlB and PNPase form a 380-kDa complex a ratio P.H. Lin-Chao S. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 16590-16595Crossref PubMed Scopus (56) Google Scholar). In a the the of the helicase of RhlB shown to be critical for PNPase binding (11Liou G.G. Chang H.Y. Lin C.S. Lin-Chao S. J. Biol. Chem. 2002; 277: 41157-41162Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar), which is with the and the concept that the configuration of the RNA degradation machinery is from to by the of the the mammalian mitochondrial RNA degradosome to a with the E. coli RNA degradosome. the the core complex of the mitochondria degradosome of budding yeast consists of and Dss1 a molar This complex configuration is different from that of E. coli and mammalian mitochondrial degradosome results suggest that yeast and mammalian by with different the of the the form of the E. coli RNA degradosome shown to contain an RNase E, and a glycolytic the of these two components have not been in yeast or mammalian mitochondrial RNA degrading RNA degradation in the mammalian mitochondria components to be It has been demonstrated in the E. coli RNA degradosome, the and the budding yeast mtEXO that the a helicase and an is to degrade structured RNAs B. Higgins C.F. Krisch H.M. Carpousis A.J. Nature. 1996; 381: 169-172Crossref PubMed Scopus (478) Google Scholar, G.G. Chang H.Y. Lin C.S. Lin-Chao S. J. Biol. Chem. 2002; 277: 41157-41162Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, M. Jedrzejczak R. Stepien P.P. Golik P. J. Mol. Biol. 2007; 372: 23-36Crossref PubMed Scopus (43) Google Scholar). the cannot stable structures of an RNA and the of the the the helicase can unwind the of the RNA in the presence of ATP, but the RNA to the a RNase have the to a the helicase and are in the entity can structured RNAs be efficiently The that these activities are always in different proteins that the individual components may have by or with binding The and mechanism of structured RNA degradation by the hSUV3-hPNPase complex cannot be the structure of the complex is However, the the from the and hSUV3-hPNPase complexes on the key of the the in the hSUV3-hPNPase complex a the of the helicase of hSUV3 for RNA which is critical for the ability of the complex to degrade as demonstrated by the However, this is not in RhlB, different in RNA the two have that the helicase and of DExH/D-box are involved in binding J. P. PubMed Scopus Google and it is that the the structure of that these were no to with the RNA the be involved in RNA can be the structure of hSUV3-hPNPase complex is It is that the a critical in the of the complex to degrade structured RNA, a process that is to by the complex binding to the 3′ of the single-stranded of the RNA to be hPNPase has RNA binding S. Chiou N.T. Schuster G. J. Biomed. Sci. 2007; 14: 523-532Crossref PubMed Scopus (57) Google Scholar), because the complex cannot degrade dsRNA hSUV3 to be in of for the the complex the single-stranded the of the RNA with hSUV3 hPNPase. a is hSUV3 the in the presence of to the hPNPase to degrade the the RNA is as in It is that these short are by yet a has not been identified in the mammalian The RNA shown in the is similar to the used in the dsRNA degradation the hSUV3-hPNPase complex can degrade long RNAs containing which may the substrates of the hSUV3-hPNPase complex the mitochondria. In as in the E. coli RNA degradosome, for efficient the long structured RNA may need to be by an endoribonuclease to the 3′ for degradation by the and RNA degradation in the mammalian mitochondria an endoribonuclease to be The presence of and the human mitochondria has been recently demonstrated S. Laufer D. Geiger D. Schuster G. Mol. Cell Biol. 2005; 25: 6427-6435Crossref PubMed Scopus (134) Google Scholar). in these RNA for It has been that of these RNAs may to mitochondrial function as suggest that the hSUV3-hPNPase complex may be involved in these RNA in the mammalian mitochondria in that in mammalian lacking hSUV3 L. G. A. V. D. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). the of and to and and and yeast lacking an of the form of the of the mitochondrial rRNA and of rRNA and (14Dziembowski A. Piwowarski J. Hoser R. Minczuk M. Dmochowska A. Siep M. van der Spek H. Grivell L. Stepien P.P. J. Biol. 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PubMed Scopus Google Scholar), it is no that hPNPase and which are shown in this to be integral components of the mitochondrial RNA-degrading be in to the mitochondrial Furthermore, by our suggest that a of SUV3 and PNPase with in not It is that a RNA-degrading complex be and is to a to do this is to hSUV3 and hPNPase in the and misfolded or RNAs are hPNPase the to form a complex with hSUV3 to remove the the and of the hSUV3-hPNPase complex in to the RNA degrading machinery serves to maintain the integrity and of the mammalian a that is are to for the hSUV3 for the and Lin for with the with