Polo-like Kinase 1 (PLK1) Regulates Interferon (IFN) Induction by MAVS

The mitochondria-bound adapter MAVS participates in IFN induction by recruitment of downstream partners such as members of the TRAF family, leading to activation of NF-κB, and the IRF3 pathways. A yeast two-hybrid search for MAVS-interacting proteins yielded the Polo-box domain (PBD) of the mitotic Polo-like kinase PLK1. We showed that PBD associates with two different domains of MAVS in both dependent and independent phosphorylation events. The phosphodependent association requires the phosphopeptide binding ability of PBD. It takes place downstream of the proline-rich domain of MAVS, within an STP motif, characteristic of the binding of PLK1 to its targets, where the central Thr234 residue is phosphorylated. Its phosphoindependent association takes place at the C terminus of MAVS. PLK1 strongly inhibits the ability of MAVS to activate the IRF3 and NF-κB pathways and to induce IFN. Reciprocally, depletion of PLK1 can increase IFN induction in response to RIG-I/SeV or RIG-I/poly(I)-poly(C) treatments. This inhibition is dependent on the phosphoindependent association of PBD at the C terminus of MAVS where it disrupts the association of MAVS with its downstream partner TRAF3. IFN induction was strongly inhibited in cells arrested in G2/M by nocodazole, which provokes increased expression of endogenous PLK1. Interestingly, depletion of PLK1 from these nocodazole-treated cells could restore, at least partially, IFN induction. Altogether, these data demonstrate a new function for PLK1 as a regulator of IFN induction and provide the basis for the development of inhibitors preventing the PLK1/MAVS association to sustain innate immunity. The mitochondria-bound adapter MAVS participates in IFN induction by recruitment of downstream partners such as members of the TRAF family, leading to activation of NF-κB, and the IRF3 pathways. A yeast two-hybrid search for MAVS-interacting proteins yielded the Polo-box domain (PBD) of the mitotic Polo-like kinase PLK1. We showed that PBD associates with two different domains of MAVS in both dependent and independent phosphorylation events. The phosphodependent association requires the phosphopeptide binding ability of PBD. It takes place downstream of the proline-rich domain of MAVS, within an STP motif, characteristic of the binding of PLK1 to its targets, where the central Thr234 residue is phosphorylated. Its phosphoindependent association takes place at the C terminus of MAVS. PLK1 strongly inhibits the ability of MAVS to activate the IRF3 and NF-κB pathways and to induce IFN. Reciprocally, depletion of PLK1 can increase IFN induction in response to RIG-I/SeV or RIG-I/poly(I)-poly(C) treatments. This inhibition is dependent on the phosphoindependent association of PBD at the C terminus of MAVS where it disrupts the association of MAVS with its downstream partner TRAF3. IFN induction was strongly inhibited in cells arrested in G2/M by nocodazole, which provokes increased expression of endogenous PLK1. Interestingly, depletion of PLK1 from these nocodazole-treated cells could restore, at least partially, IFN induction. Altogether, these data demonstrate a new function for PLK1 as a regulator of IFN induction and provide the basis for the development of inhibitors preventing the PLK1/MAVS association to sustain innate immunity. The cellular innate immune response is triggered by a variety of microbial pathogens as an essential mechanism to limit the initial spread of these infections and involves the production of inflammatory cytokines and type I interferons (IFNα/β) 6The abbreviations used are: IFNinterferonMAVSmitochondrial antiviral signalingCARDcaspase activation and recruitment domainRIPreceptor-interacting proteinTRAFtumor necrosis factor receptor-associated factorTBK1TANK-binding kinase 1NF-κBnuclear factor-κBIκBα(inhibitor of κB) αIKKIκB (inhibitor of κB) kinaseIRF3interferon regulatory factor-3IL-8interleukin-8ISG56interferon-stimulated gene 56dsRNAdouble-stranded RNAsiRNAsilencing RNARSVRous Sarcoma VirusCMVcytomegalovirusGal4galactosidase transcription factorCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidFLfull-lengthWTwild typeGSTglutathione S-transferase. (1Barton G.M. Medzhitov R. Science. 2003; 300: 1524-1525Crossref PubMed Scopus (1059) Google Scholar). In the particular case of infections with RNA viruses, IFN-α/β induction occurs following interaction of viral RNAs with two cytosolic CARD-containing DE/xDH RNA helicases: RIG-I (retinoic acid-induced gene-I (2Yoneyama M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (3122) Google Scholar) or MDA-5 (melanoma differentiation-associated gene-5) (3Kang D.C. Gopalkrishnan R.V. Wu Q. Jankowsky E. Pyle A.M. Fisher P.B. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 637-642Crossref PubMed Scopus (516) Google Scholar, 4Andrejeva J. Childs K.S. Young D.F. Carlos T.S. Stock N. Goodbourn S. Randall R.E. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 17264-17269Crossref PubMed Scopus (818) Google Scholar). RIG-I is activated upon recognition of single-stranded RNA (ssRNAs) with uncapped 5′-triphosphate ends, specific homopolymeric RNA motifs, or short dsRNA. In contrast, activation of MDA5 occurs upon recognition of long dsRNA (5Hornung V. Ellegast J. Kim S. Brzózka K. Jung A. Kato H. Poeck H. Akira S. Conzelmann K.K. Schlee M. Endres S. Hartmann G. Science. 2006; 314: 994-997Crossref PubMed Scopus (1896) Google Scholar, 6Pichlmair A. Schulz O. Tan C.P. Näslund T.I. Liljeström P. Weber F. Reis e. Sousa C. Science. 2006; 314: 997-1001Crossref PubMed Scopus (1771) Google Scholar, 7Saito T. Owen D.M. Jiang F. Marcotrigiano J. Gale Jr., M. Nature. 2008; 454: 523-527Crossref PubMed Scopus (578) Google Scholar, 8Kato H. Takeuchi O. Mikamo-Satoh E. Hirai R. Kawai T. Matsushita K. Hiiragi A. Dermody T.S. Fujita T. Akira S. J. Exp. Med. 2008; 205: 1601-1610Crossref PubMed Scopus (1160) Google Scholar, 9Saito T. Gale Jr., M. J. Exp. Med. 2008; 205: 1523-1527Crossref PubMed Scopus (118) Google Scholar). 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PubMed Google Scholar). and by in was of a a the to The from the yeast and in was in the or the to as and The of MAVS was from the and the to The the was by The with the by on the The and the of MAVS the and The IFN-β and A. N. R. C. Akira S. M. Fujita T. J. J. 2005; PubMed Scopus Google Scholar). and from was from The was by by and the from R. The RIG-I was in M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (3122) Google and cells in with and cells as A. N. R. C. Akira S. M. Fujita T. J. J. 2005; PubMed Scopus Google Scholar). to the with from and L. 2006; PubMed Scopus Google was as in A. N. R. C. Akira S. M. Fujita T. J. J. 2005; PubMed Scopus Google IFN-β cells with of and of of the PLK1 with MAVS or PLK1 of different of MAVS. for and or with The as in A. N. R. C. Akira S. M. Fujita T. J. J. 2005; PubMed Scopus Google as the of to of cells with of and of of the binding domain of with the Polo-box domain of of the of MAVS with the or The as by the as the of with and in A or of and inhibitors protein at inhibitors The protein was by as A. N. R. C. Akira S. M. Fujita T. J. J. 2005; PubMed Scopus Google Scholar). at with the and in the of for The and the proteins at and by and with by the at in and for in to 1 of and in protein to with the by the proteins to a and the of proteins in the was by the proteins of the to an by on a cellular RNA was by to the The of the used for the transcription of and in M. E. S. A. P. J. 2006; PubMed Scopus Google The of the used for are: The on 1 of RNA and was on a with of the in a of and of of and or The of to the of The of RNA as of A yeast two-hybrid R. N. M. Science. PubMed Scopus Google Scholar) was to search for MAVS-interacting We used a MAVS of its domain to and interaction with the of with a MAVS was used as a The mitotic Polo-like kinase PLK1 Nat. 2004; 5: PubMed Scopus Google Scholar) was as a partner for MAVS with two members of the necrosis factor receptor-associated factor family, and data in with from a yeast two-hybrid MAVS as K.J. 2005; PubMed Scopus Google Scholar). The of the PLK1 to its PBD. The interaction MAVS and the was in cells a two-hybrid in which the was with the domain of the MAVS was to the of both an of a the of the by the yeast two-hybrid and showed that MAVS could with as as PLK1 of PLK1 is to to the Nat. 2004; 5: PubMed Scopus Google Scholar). to MAVS and PLK1 could at the endogenous the of PLK1 and MAVS expression as a function of the in different and cells at by K. R. N. Jiang J. 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Hirai R. Kawai T. Matsushita K. Hiiragi A. Dermody T.S. Fujita T. Akira S. J. Exp. Med. 2008; 205: 1601-1610Crossref PubMed Scopus (1160) Google increase association with This that the association MAVS and PLK1 place of MAVS PLK1 of its by a phosphopeptide binding in its Polo-box Through motif, it can or which by specific This phosphopeptide binding ability of PLK1 is dependent on and J. J. 2003; PubMed Scopus Google Scholar, P. K. 2003; PubMed Scopus Google Scholar, G. S. E. G. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). the of the association of PLK1 with MAVS, the and the or and their ability to MAVS. of MAVS to both and was which that the PLK1/MAVS association could different MAVS that MAVS at two different an N-terminal domain and a domain and The MAVS N-terminal domain associates to the with phosphopeptide binding of the of binding of to different MAVS to of MAVS to a the the the MAVS domain of the in the and to could it to the on type of the MAVS of their domain and to the and to the This that binding of PLK1 to the domain of MAVS on the domain of MAVS on the of MAVS at the to a the of both the domain and the can in with its ability to the This in the of its a that to to the Altogether, these that PLK1 its Polo-box domain to with two domains of MAVS of the proline-rich of MAVS and at the domain of MAVS in We the of MAVS phosphorylation on its interaction with PLK1. two MAVS and of the in cells in the of PLK1 or and the with to MAVS The that the association of or MAVS with PLK1 or was strongly inhibited by the In contrast, association of the PLK1 with was data that PLK1 associates with two domains of MAVS, which on the phosphopeptide binding of PLK1 and on a phosphorylation and which is independent of We that the PBD of PLK1 associates to the domain of MAVS This domain and that could as phosphorylation In its the PLK1 phosphopeptide binding P. K. 2003; PubMed Scopus Google Scholar). of the MAVS or strongly their ability to the and with and The association in and is to PLK1 interaction with the domain of MAVS. the which its ability to PLK1 its C to PLK1 the and of the residue within the STP to for the binding of the Polo-box the residue that the with P. K. 2003; PubMed Scopus Google Scholar). MAVS the or to a strongly ability to and of the Thr234 residue to the or could the ability of to MAVS or It is that the is to as a and that phosphorylation of Thr234 is for recognition by Altogether, these that the and Thr234 of MAVS an in the recruitment of PLK1 to MAVS. PLK1 its phosphopeptide binding ability to MAVS, to MAVS could in We MAVS in of cells MAVS or the or of of these was or in the of PLK1 to of its R. R. H. Nat. PubMed Scopus Google Scholar). a for used that kinase can MAVS S. M. M. Sun Q. J. T. S. A. R. J. PubMed Scopus Google Scholar). The that MAVS was and that its phosphorylation was increased in the of was was PLK1 could increase the phosphorylation of was in the of PLK1 strongly in the of The ability of to the C terminus of MAVS was the of and in a the in phosphorylation of different of that by the of a or an residue at We that the and the The a and specific increase in the phosphorylation of the of residue in MAVS phosphorylation Altogether, these for the that MAVS can in In the phosphorylation of the residue at the N-terminal domain of MAVS can provide the to PLK1 the phosphopeptide binding MAVS is an factor of the the of PLK1 on MAVS PLK1 ability to induce in with a K.J. 2005; PubMed Scopus Google Scholar). in the of MAVS, PLK1 strongly inhibited the of the promoter as as the induction of the endogenous and used as of the and NF-κB signaling The of PLK1 on the was in response to by of the the (5Hornung V. Ellegast J. Kim S. Brzózka K. Jung A. Kato H. Poeck H. Akira S. Conzelmann K.K. Schlee M. Endres S. Hartmann G. Science. 2006; 314: 994-997Crossref PubMed Scopus (1896) Google Scholar). A of the promoter by the was strongly inhibited in the of PLK1 A inhibition was on endogenous by We used MAVS the a of the domain to the of the two domains on inhibition of MAVS. MAVS and the MAVS MAVS MAVS and the MAVS in the of PLK1 or and for their ability to induce an In these for their ability to PLK1 or The binding of both PLK1 and to MAVS and and inhibition of MAVS by PLK1 A and In these that is as as PLK1 in the of MAVS PLK1 to MAVS and MAVS and of its ability to the of these MAVS In contrast, PLK1 was in binding MAVS and could its could MAVS with as with MAVS and was to MAVS was to MAVS as as MAVS could was to to MAVS and was to its Altogether, these that both domains of MAVS in the inhibition of MAVS by PLK1. A of the interaction and on IFN induction is in the The ability of PLK1 to the IFN induction was by the that depletion of endogenous PLK1 by in an increase in MAVS the of the depletion of PLK1 on the RIG-I signaling by of RIG-I and of the IFN signaling with The that in where the viral strongly RIG-I and IFN depletion of PLK1 signaling MAVS to on its association with members of the TRAF family, such as the and In is in the activation of the IRF3 which is essential for IFN induction G. A. G. J. 2006; PubMed Scopus Google Scholar). We the of on the a it to the association MAVS and R. J. P. Sun Q. L. S. P. E. J. J. 2006; PubMed Scopus Google Scholar, S. M. M. Sun Q. J. T. S. A. R. J. PubMed Scopus Google Scholar). We of MAVS and in the of of to a of the on the association that MAVS to recruitment of downstream partners M. F. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). We showed that PLK1 was to MAVS that PLK1 can MAVS of its of This is in with the data in 1 where showed that binding of PLK1 to MAVS was increased in the of We the of of on the association of with the two and of the PLK1 binding that associates with and with M. and M. in with the data from G. A. G. J. 2006; PubMed Scopus Google Scholar). The and of to the MAVS used in The of the binding domain of MAVS in a Interestingly, was to strongly the interaction of to the domain This was in with in which of MAVS in of data demonstrate that mechanism for the of PLK1 in IFN induction is the interaction of its PBD at the domain of MAVS and involves of TRAF3. to PLK1/MAVS interaction to could the innate immune response or in the of PLK1. or from their endogenous to and MAVS signaling was with RIG-I and The that depletion of PLK1 can increase the IFN induction as in where was used as an for was used of to the that of the by the of the upon In that strongly increased the expression of PLK1 and to a inhibition of IFN induction. Interestingly, depletion of PLK1 was to IFN induction data that with the of an increase in PLK1 that can with the innate immune signaling pathways. A search for partners to the adapter MAVS by a yeast two-hybrid the mitotic Polo-like kinase PLK1. We that PLK1 with MAVS its Polo-box domain and with induction of IFN. of the of PLK1 is to its its in a phosphodependent a that and of PLK1 to specific Science. 2003; PubMed Scopus Google Scholar). that for PLK1 by and D.M. M. J. K. S. J. PubMed Scopus Google Scholar). showed that MAVS as a for PLK1 on the that association of MAVS with PLK1 requires the phosphopeptide binding of PLK1 and on in phosphorylation We could specific association to the N-terminal of MAVS, and This an that could to the phosphopeptide by PBD P. K. 2003; PubMed Scopus Google Scholar, D.M. M. J. K. S. J. PubMed Scopus Google and showed the of both MAVS and Thr234 in its association with PLK1 their to the association of Thr234 or to the could association of MAVS to and This that the of a essential for MAVS to as a for PLK1. data showed that MAVS can in on its domain and that the its of phosphorylation We that the phosphorylation of was increased in the of PLK1. for the phosphorylation of MAVS at its PLK1 binding STP We that PLK1 was to to the domain of MAVS, of its phosphopeptide binding ability and in a phosphoindependent This binding of MAVS domain to a different of or to the of MAVS at the a binding of to the protein A. H. G. J. 2008; PubMed Scopus Google Scholar). In of the of MAVS in IFN the of PLK1 on signaling PLK1 as a of the ability to induce IFN the downstream NF-κB and IRF3 signaling pathways. PLK1 was to IFN induction in response to a viral such as and of its expression could IFN induction in response to MAVS. MAVS in its N-terminal PLK1 binding domain PLK1 and is to its MAVS in its PLK1 binding domain PLK1. that the recruitment of PLK1 to the N-terminal domain of MAVS its phosphopeptide PLK1 the C terminus of MAVS a different on its PBD This with the recruitment of and MAVS A of the PLK1/MAVS association is in from its on MAVS of PLK1 was to increase induction of IFN in response to MAVS In PLK1 to the of of the IFN induction at the or downstream of MAVS. the RNA to RIG-I and of the a to the domain of MAVS and can with the binding of T. Hirai R. Owen Akira S. Fujita T. Gale Jr., M. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). a domain and to the with MAVS and inhibits MAVS Sun L. Chen Nature. 2008; PubMed Scopus Google Scholar). A an to and the on in its from the downstream signaling and as a regulator of innate immune N. Q. S. R. C. M. E. G. Science. PubMed Scopus Google Scholar). of PLK1 was to increase MAVS its inhibited MAVS. PLK1 expression the In the of that which can increase the expression of PLK1 and its association with MAVS, can strongly IFN induction. of PLK1 could IFN that at the endogenous PLK1 a in the of innate immunity. is to with the of PLK1 its kinase domain to of and of their association in or G. J. PubMed Scopus Google Scholar). It that can the 2008; 5: PubMed Scopus Google Scholar). is to its kinase PLK1 with MAVS its Polo-box domain and MAVS PLK1 in cells as a of K. A. Nat. 2006; 6: PubMed Scopus Google Scholar). a the of PLK1 expression with that to and the cells cells from with viral both of and an that to and P. F. J. 2004; PubMed Scopus Google Scholar). Interestingly, in the case of can increase viral cells in the of the and in and In it was to of the yeast of in or in the F. F. S. S. J. 2004; PubMed Scopus Google Scholar). The that a of PLK1 its association with MAVS and of innate immune response to The proteins the of cellular such as and to and to in to the of and A. N. 2004; PubMed Scopus Google Scholar). an association PLK1 and the domain of MAVS and its on MAVS data the new that of the of the ability of PLK1 to the cells is its ability to the innate immune of the We that of cells with such as nocodazole, can IFN induction that of IFN induction could by PLK1 from the It that the of with PLK1 the and an E. M. K. PubMed Scopus Google Scholar). It is that PLK1 its of MAVS and induction of which In to at PLK1 in to the kinase of PLK1 such as the K. A. Nat. 2006; 6: PubMed Scopus Google Scholar, M. M. A. P. M. M. P. S. J. M. N. PubMed Scopus Google Scholar). The of inhibitors that the Polo-box domain to of PLK1 to its cellular partners is In the to PLK1 mitotic and in cells J. A. K. T. 2008; PubMed Scopus Google Scholar). for the that the PLK1 inhibits IFN induction at the of MAVS its inhibitors that binding of PLK1 to MAVS of for in in with the of to the ability of the cells to an innate immune We for the of the PLK1 for of the and and for The of with

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