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Vaccinia Virus F1L Protein Promotes Virulence by Inhibiting Inflammasome Activation

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Vaccinia Virus F1L Protein Promotes Virulence by Inhibiting Inflammasome Activation Vaccinia virus F1L protein promotes virulence by inhibiting inflammasome activation Motti Gerlica,1, Benjamin Faustina,1, Antonio Postigob, Eric Chi-Wang Yua, Martina Proella,c, Naran Gombosurena, Maryla Krajewskaa, Rachel Flynnd, Michael Croftd, Michael Wayb, Arnold Satterthwaita, Robert C. Liddingtona, Shahram Salek-Ardakanid,2, Shu-ichi Matsuzawaa, and John C. Reeda,3 aSanford-Burnham Medical Research Institute, La Jolla, CA 92037; bCancer Research UK London Research Institute, London WC2A 3LY, United Kingdom; cDepartment of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria; and dDivision of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 Edited by Elliott Kieff, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, and approved March 22, 2013 (received for review October 8, 2012) Host innate immune responses to DNA viruses involve members of Bcl-2 family members, several of these viral homologs were dis- the nucleotide-binding domain, leucine-rich repeat and pyrin do- covered to adopt an α-helical fold similar to Bcl-2 (13-17). However, main containing protein (NLRP) family, which form “inflamma- not all of the VACV-encoded Bcl-2–like proteins possess anti- somes” that activate caspase-1, resulting in proteolytic activation apoptotic activity (18), implying that they have other functions. of cytokines interleukin (IL)-1β and IL-18. We hypothesized that Indeed, the viral Bcl-2–like proteins A52, B14, N1, and K7 were DNA viruses would target inflammasomes to overcome host de- found to inhibit NF-κB pathways at various checkpoints (11). fense. A Vaccinia virus (VACV) B-cell CLL/lymphoma 2 (Bcl-2) homo- Recently, cellular Bcl-2 family proteins have been demonstrated log, F1L, was demonstrated to bind and inhibit the NLR family to interact with NLRs to impact innate immunity responses member NLRP1 in vitro. Moreover, infection of macrophages in cul- (19, 20). We therefore hypothesized that viral Bcl-2 homologs ture with virus lacking F1L (ΔF1L) caused increased caspase-1 activa- encoded by VACV might similarly inhibit inflammasome signaling tion and IL-1β secretion compared with wild-type virus. Virulence of during infection. Our data provide evidence that the viral Bcl-2 ΔF1L virus was attenuated in vivo, causing altered febrile responses, homolog F1L (but not N1L) is a suppressor of NLR family proteins increased proteolytic processing of caspase-1, and more rapid in- involved in IL-1β activation. Furthermore, by testing genetically flammation in lungs of infected mice without affecting cell death engineered VACV in a mouse model, our findings also demon- or virus replication. Furthermore, we found that a hexapeptide from strate a role for NLR suppression in the pathogenic mechanism by F1L is necessary and sufficient for inhibiting the NLRP1 inflamma- which F1L contributes to virulence in vivo. some in vitro, thus identifying a peptidyl motif required for binding and inhibiting NLRP1. The functional importance of this NLRP1-bind- Results ing motif was further confirmed by studies of recombinant ΔF1L VACV Bcl-2 Homolog, F1L, Binds NLRP1. Of the viral Bcl-2 homologs viruses reconstituted either with the wild-type F1L or a F1L mutant encoded by VACV, only F1L and N1L have been reported to that fails to bind NLRP1. Cellular infection with wild-type F1L recon- display antiapoptotic activity and to bind proapoptotic members of stituted virus-suppressed IL-1β production, whereas mutant F1L did the cellular Bcl-2 family such as Bcl-2–associated X protein (Bax) not. In contrast, both wild-type and mutant versions of F1L equally (14, 18, 21). We explored the ability of F1L to bind various NLR suppressed apoptosis. In vivo, the NLR nonbinding F1L mutant virus family members, making comparisons with apoptosis-associated exhibited an attenuated phenotype similar to ΔF1L virus, thus con- speck-like protein containing a caspase recruitment domain (ASC), firming the importance of F1L interactions with NLRP1 for viral path- absent in melanoma 2 (AIM2), and other proteins involved in in- ogenicity in mice. Altogether, these findings reveal a unique viral nate immune defense against viruses. In cell transfection experi- mechanism for evading host innate immune responses. ments, F1L coimmunoprecipitated with NLRP1, a NLR member inhibited by Bcl-2 and Bcl-XL (20), but not with NLR family virus infection | virology | innate immunity | poxviruses members NLRP3 and nucleotide-binding oligomerization domain- containing protein 2 (NOD2) (NLRC2) and not with AIM2 or ASC (Fig. 1A and Fig. S1A). Colocalization of F1L with NLRP1 ucleotide-binding domain and leucine-rich repeat containing was also demonstrated by immunofluorescence confocal micros- Nreceptors (NLRs) constitute a large family of intracellular copy (Fig. S1C). In contrast to F1L, the viral N1L protein did not innate immunity proteins involved in host defense (1). Upon ac- associate with NLRP1 as determined by coimmunoprecipitation tivation, NLRs form large protein complexes called “inflamma- fl ” (co-IP) assay and by immuno uorescence confocal microscopy somes that bind and activate caspase-1 family proteases, resulting (Fig. 1A and Fig. S1C). in proteolytic activation of proinflammatory cytokines (which in- fi – β – The interaction of F1L with NLRP1 was further con rmed by clude pro IL-1 and pro IL-18) and sometimes causing a caspase- in vitro protein binding assays, using GST-tagged recombinant 1–dependent form of cell death known as pyroptosis (2, 3). Members of the NLR family possess a conserved architecture that includes leucine-rich repeats (LRRs) that are thought to act as Author contributions: M.G., B.F., M.W., S.M., and J.C.R. designed research; M.G., B.F., A.P., receptors for various pathogen-derived molecules. Certain NLRs, M.P., R.F., S.S.-A., and S.M. performed research; M.G., B.F., A.P., E.C.-W.Y., N.G., M.W., and several other types of innate immunity proteins, are involved A.S., and R.C.L. contributed new reagents/analytic tools; M.G., B.F., A.P., M.P., M.K., M.C., in detecting foreign double-stranded DNA (dsDNA) in cells, a M.W., S.S.-A., and J.C.R. analyzed data; and M.G., B.F., and J.C.R. wrote the paper. function linked to host defense against DNA viruses (4–9). The authors declare no conflict of interest. Poxviruses constitute a viridae known for their large, complex This article is a PNAS Direct Submission. DNA genomes. Vaccinia virus (VACV) is a prototypical member of 1M.G. and B.F. contributed equally to this work. the poxvirus family, which replicates in the cytoplasm of host cells 2Present address: Department of Pathology, Immunology, and Laboratory Medicine, Uni- and encodes numerous proteins that manipulate the host response versity of Florida, Gainesville, FL 32610. to infection (10). VACV encodes several viral homologs of the 3To whom correspondence should be addressed. E-mail: reedoffice@sanfordburnham. cellular antiapoptotic protein B-cell CLL/lymphoma 2 (Bcl-2), org. including A46R, A52R, B14R, C1L, C6L, C16/B22R, F1L, K7R, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. N1L, and N2L (11, 12). Despite low sequence similarity to cellular 1073/pnas.1215995110/-/DCSupplemental. 7808–7813 | PNAS | May 7, 2013 | vol. 110 | no. 19 www.pnas.org/cgi/doi/10.1073/pnas.1215995110 Downloaded by guest on September 28, 2021 A B reconstituted the NLRP1 inflammasome in vitro by using purified recombinant proteins, showing that the combination of NLRP1 ligand muramyl dipeptide (MDP) and ATP induces NLRP1 6 oligomerization and caspase-1 activation in a Bcl-2/Bcl-X - 5 L suppressible manner (22, 23). Adding recombinant F1L to these in 4 180 vitro reactions suppressed NLRP1-driven caspase-1 activity, whereas 3 N1L and GST control proteins did not (Fig. 1B). Comparison of 2 37 various fragments of F1L (truncated from the N terminus) sug- 1 (fold stimulation) gested that residues between aa 24 and 48 of F1L are required for 180 Caspase-1 activity 0 NLRP1 suppression (Fig. 1B), which correlated with binding to CNTL N1L GST (24-206) NLRP1 (Fig. S2A). Additional experiments using a GST-F1L F1L (1-206)L (48-206)L (74-206) 37 F1L F1 F1 F1L (90-206) (1–47) fusion protein showed that the first 47 amino acids of F1L are sufficient for suppressing NLRP1 activity in vitro (Fig. 1C). +MDP/ATP C 175 Unstimulated D 350 Next, we chemically synthesized peptides (Table S1) corre- 150 300 sponding to residues 1–47 of F1L and various shorter segments, 125 250 examining their effects on the reconstituted NLRP1 inflamma- 100 200 some in vitro. The addition of the F1L peptide 1–47 and shorter 75 150 peptides (residues 22–47 and 27–37) inhibited NLRP1-mediated (RFU/min) 50 (RFU/min) 100 caspase-1 activation to baseline levels (Fig. 1D and Fig. S2B). Caspase-1 activity 25 Caspase-1 activity 50 0 However, these F1L peptides were neither active against the 0 Δ N1L F1L N1L F1L gain-of-function mutant NLRP LRR (which does not bind F1L CNTLBcl-2 CNTLBcl-2 fi F1L(1-47)F1L(1-35) F1L(1-47)F1L(1-35) No peptide protein) nor against puri ed active recombinant caspase-1, F1Lp (27-37)F1Lp (32-37)F1Lp (22-35)F1Lp (22-34) showing NLRP1 dependence (Fig. S2 C and D). Furthermore, the F1L peptide (22–47) binds to NLRP1, as determined by EF120 350 fluorescence polarization assay using a fluorochrome-conjugated 100 300 E fl 80 250 peptide (Fig. S2 ). In addition to using a uorigenic peptide 200 substrate (Ac-WEHD-AMC) to monitor caspase-1 activity, we 60 150 also assessed NLRP1-induced proteolytic processing of caspase-1 40 (RFU/min) 100 ATP binding ATP (% inhibition) by immunoblotting, showing that both synthetic F1L peptide 20 50 – – Caspase-1 activity (22 47) and recombinant GST-F1L (1 47) protein inhibited 0 0 proteolytic processing of caspase-1 driven by NLRP1, but not by N1L F1L C7A GST L V33A 32-3717-3716-19 Δ F F1 F1L mutant constitutively active NLRP1 LRR (Fig.
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