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Degradation triggers the alarm

Inflammasomes are multiprotein complexes that orchestrate proinflammatory cytokine secretion and cell death. Proteases such as anthrax lethal factor can activate an inflammasome known as NLRP1B, but the mechanism for this activation has been unclear. Chui et al. used genome-wide knockout screens to show that proteolysis of NLRP1B by lethal factor induces proteasomal degradation of the amino-terminal domains of NLRP1B and eventual cell death. Sandstrom et al. found that degradation of the amino-terminal domains of NLRP1B resulted in the release of a carboxyl-terminal fragment that activates caspase-1. This process, called “functional degradation,” allows the immune system to detect pathogen-associated activities, much as it recognizes pathogen-associated antigens.
Science, this issue p. 82, p. eaau1330

Structured Abstract

INTRODUCTION

Detection of pathogens by the innate immune system is an essential first step in successful host defense against infection. Pathogens are typically detected by germline-encoded innate immune receptors that bind directly to pathogen-derived ligands. Here, we describe a distinct mechanism of pathogen-sensing mediated by an immune sensor protein called NLRP1B. NLRP1B is not known to bind directly to a pathogen ligand but instead appears to detect the enzymatic activity of lethal factor (LF), a protease toxin produced by the anthrax bacterium, Bacillus anthracis. LF was previously shown to cleave NLRP1B at its N terminus, leading to activation of a multiprotein complex called an inflammasome. Inflammasomes initiate immune responses by activating a proinflammatory protease called caspase-1. However, the mechanism by which cleavage of NLRP1 results in inflammasome assembly was unknown.

RATIONALE

NLRP1B is a member of the nucleotide-binding domain leucine-rich repeat (NLR) protein superfamily. Unlike other NLRs, NLRP1B encodes a C-terminal function-to-find domain (FIIND) followed by a caspase activation and recruitment domain (CARD). The FIIND undergoes constitutive autoproteolytic processing, which cleaves NLRP1B into two separate polypeptides, which nevertheless remain noncovalently associated. The functional importance of this distinctive protein architecture has been a long-standing mystery. Also unexplained is the prior observation that NLRP1B activation requires the activity of the proteasome. We therefore sought a mechanism that explains how N-terminal cleavage by LF, FIIND autoprocessing, and the proteasome cooperate to initiate NLRP1B inflammasome formation.

RESULTS

We found that N-terminal cleavage of NLRP1B by LF protease results in destabilization of NLRP1B and its degradation by the proteasome. Paradoxically, NLRP1B inflammasome activation inversely correlated with the stability of the NLRP1B protein after protease cleavage: Proteasome inhibitors stabilized cleaved NLRP1B and prevented NLRP1B inflammasome activation. Indeed, we found that targeted degradation of NLRP1B induced inflammasome activation, even in the absence of protease cleavage, indicating that proteasomal degradation is not only necessary but also sufficient for NLRP1B inflammasome activation. FIIND autoprocessing was required for NLRP1B activation regardless of whether activation occurred via LF cleavage or targeted degradation. To explain these observations, we hypothesized that the function of the proteasome during NLRP1B activation is to degrade the N-terminal domains of NLRP1B, leading to release of a bioactive C-terminal CARD-containing fragment. Consistent with this model, we found that the C-terminal CARD-containing fragment of NLRP1B is sufficient to self-assemble, recruit caspase-1, and form a functional inflammasome. LF protease treatment resulted in specific degradation of the N-terminal domains of NLRP1B, whereas the liberated C-terminal domain associated with inflammasome puncta in cells. We refer to this proteasome-dependent mechanism of NLRP1B inflammasome activation as functional degradation. Similar conclusions were reached independently by Bachovchin and colleagues (this issue).
The functional degradation model raised the possibility that NLRP1B could sense not only proteases but also any pathogen effector that induced proteasomal degradation of NLRP1B. In accord with this prediction, we identified IpaH7.8, an E3 ubiquitin ligase secreted by the pathogen Shigella flexneri, as another activator of NLRP1B. IpaH7.8 directly and specifically ubiquitylates NLRP1B, leading to NLRP1B degradation and inflammasome activation in Shigella-infected macrophages.

CONCLUSION

We speculate that functional degradation may also explain the activation of other FIIND-containing proteins, such as CARD8 and PIDD1. More broadly, our results reveal a mechanism, distinct from recognition of pathogen-associated ligands, by which hosts can initiate protective immune responses via detection of diverse pathogen-associated activities.
Diverse pathogen enzymes activate the NLRP1B inflammasome by functional degradation.
NLRP1B autoprocesses within the FIIND to generate two noncovalently associated fragments. Cleavage of NLRP1B by anthrax LF, or ubiquitylation by Shigella IpaH7.8, results in proteasome-mediated degradation of NLRP1B, leading to release of the bioactive C-terminal fragment and inflammasome assembly. LRR, leucine-rich repeat; NBD, nucleotide binding domain; Nt, N terminus; Ub, ubiquitylation.

Abstract

Inflammasomes are multiprotein platforms that initiate innate immunity by recruitment and activation of caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-terminal fragment that is a potent caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our functional degradation model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.

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Supplementary Material

Summary

Figs. S1 to S7
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References and Notes

1
C. A. Janeway Jr., ., Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).
2
J. D. Jones, J. L. Dangl, The plant immune system. Nature 444, 323–329 (2006).
3
J. M. Blander, L. E. Sander, Beyond pattern recognition: Five immune checkpoints for scaling the microbial threat. Nat. Rev. Immunol. 12, 215–225 (2012).
4
L. K. Chung, Y. H. Park, Y. Zheng, I. E. Brodsky, P. Hearing, D. L. Kastner, J. J. Chae, J. B. Bliska, The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome. Cell Host Microbe 20, 296–306 (2016).
5
A. M. Keestra, M. G. Winter, J. J. Auburger, S. P. Frässle, M. N. Xavier, S. E. Winter, A. Kim, V. Poon, M. M. Ravesloot, J. F. T. Waldenmaier, R. M. Tsolis, R. A. Eigenheer, A. J. Bäumler, Manipulation of small Rho GTPases is a pathogen-induced process detected by NOD1. Nature 496, 233–237 (2013).
6
A. M. Keestra-Gounder, M. X. Byndloss, N. Seyffert, B. M. Young, A. Chávez-Arroyo, A. Y. Tsai, S. A. Cevallos, M. G. Winter, O. H. Pham, C. R. Tiffany, M. F. de Jong, T. Kerrinnes, R. Ravindran, P. A. Luciw, S. J. McSorley, A. J. Bäumler, R. M. Tsolis, NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532, 394–397 (2016).
7
D. Ratner, M. P. A. Orning, M. K. Proulx, D. Wang, M. A. Gavrilin, M. D. Wewers, E. S. Alnemri, P. F. Johnson, B. Lee, J. Mecsas, N. Kayagaki, J. D. Goguen, E. Lien, The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLOS Pathog. 12, e1006035 (2016).
8
R. E. Vance, R. R. Isberg, D. A. Portnoy, Patterns of pathogenesis: Discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe 6, 10–21 (2009).
9
H. Xu, J. Yang, W. Gao, L. Li, P. Li, L. Zhang, Y.-N. Gong, X. Peng, J. J. Xi, S. Chen, F. Wang, F. Shao, Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513, 237–241 (2014).
10
M. F. Fontana, S. Banga, K. C. Barry, X. Shen, Y. Tan, Z.-Q. Luo, R. E. Vance, Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila. PLOS Pathog. 7, e1001289 (2011).
11
F. Martinon, K. Burns, J. Tschopp, The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10, 417–426 (2002).
12
P. Broz, V. M. Dixit, Inflammasomes: Mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
13
J. Chavarría-Smith, R. E. Vance, The NLRP1 inflammasomes. Immunol. Rev. 265, 22–34 (2015).
14
V. A. Rathinam, K. A. Fitzgerald, Inflammasome Complexes: Emerging Mechanisms and Effector Functions. Cell 165, 792–800 (2016).
15
E. D. Boyden, W. F. Dietrich, Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet. 38, 240–244 (2006).
16
J. Chavarría-Smith, R. E. Vance, Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLOS Pathog. 9, e1003452 (2013).
17
K. A. Hellmich, J. L. Levinsohn, R. Fattah, Z. L. Newman, N. Maier, I. Sastalla, S. Liu, S. H. Leppla, M. Moayeri, Anthrax lethal factor cleaves mouse nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLOS ONE 7, e49741 (2012).
18
J. L. Levinsohn, Z. L. Newman, K. A. Hellmich, R. Fattah, M. A. Getz, S. Liu, I. Sastalla, S. H. Leppla, M. Moayeri, Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLOS Pathog. 8, e1002638 (2012).
19
A. D’Osualdo, C. X. Weichenberger, R. N. Wagner, A. Godzik, J. Wooley, J. C. Reed, CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. PLOS ONE 6, e27396 (2011).
20
J. N. Finger, J. D. Lich, L. C. Dare, M. N. Cook, K. K. Brown, C. Duraiswami, J. Bertin, P. J. Gough, Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J. Biol. Chem. 287, 25030–25037 (2012).
21
B. C. Frew, V. R. Joag, J. Mogridge, Proteolytic processing of Nlrp1b is required for inflammasome activity. PLOS Pathog. 8, e1002659 (2012).
22
S. L. Fink, T. Bergsbaken, B. T. Cookson, Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl. Acad. Sci. U.S.A. 105, 4312–4317 (2008).
23
R. C. Squires, S. M. Muehlbauer, J. Brojatsch, Proteasomes control caspase-1 activation in anthrax lethal toxin-mediated cell killing. J. Biol. Chem. 282, 34260–34267 (2007).
24
G. Tang, S. H. Leppla, Proteasome activity is required for anthrax lethal toxin to kill macrophages. Infect. Immun. 67, 3055–3060 (1999).
25
K. E. Wickliffe, S. H. Leppla, M. Moayeri, Killing of macrophages by anthrax lethal toxin: Involvement of the N-end rule pathway. Cell. Microbiol. 10, 1352–1362 (2008).
26
K. E. Wickliffe, S. H. Leppla, M. Moayeri, Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell. Microbiol. 10, 332–343 (2008).
27
F. L. Zhong, O. Mamaï, L. Sborgi, L. Boussofara, R. Hopkins, K. Robinson, I. Szeverényi, T. Takeichi, R. Balaji, A. Lau, H. Tye, K. Roy, C. Bonnard, P. J. Ahl, L. A. Jones, P. J. Baker, L. Lacina, A. Otsuka, P. R. Fournie, F. Malecaze, E. B. Lane, M. Akiyama, K. Kabashima, J. E. Connolly, S. L. Masters, V. J. Soler, S. S. Omar, J. A. McGrath, R. Nedelcu, M. Gribaa, M. Denguezli, A. Saad, S. Hiller, B. Reversade, Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell 167, 187–202.e17 (2016).
28
J. Chavarría-Smith, P. S. Mitchell, A. M. Ho, M. D. Daugherty, R. E. Vance, Functional and Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation. PLOS Pathog. 12, e1006052 (2016).
29
J. Neiman-Zenevich, K. C. Liao, J. Mogridge, Distinct regions of NLRP1B are required to respond to anthrax lethal toxin and metabolic inhibition. Infect. Immun. 82, 3697–3703 (2014).
30
A. Bachmair, D. Finley, A. Varshavsky, In vivo half-life of a protein is a function of its amino-terminal residue. Science 234, 179–186 (1986).
31
X. Lucas, A. Ciulli, Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies. Curr. Opin. Struct. Biol. 44, 101–110 (2017).
32
A. J. Chui, M. C. Okondo, S. D. Rao, K. Gai, A. R. Griswold, D. C. Johnson, D. P. Ball, C. Y. Taabazuing, E. L. Orth, B. A. Vittimberga, D. A. Bachovchin, N-terminal degradation activates the NLRP1B inflammasome. Science 364, 82–85 (2019).
33
D. K. Gonda, A. Bachmair, I. Wünning, J. W. Tobias, W. S. Lane, A. Varshavsky, Universality and structure of the N-end rule. J. Biol. Chem. 264, 16700–16712 (1989).
34
A. Varshavsky, The N-end rule pathway and regulation by proteolysis. Protein Sci. 20, 1298–1345 (2011).
35
A. J. Holland, D. Fachinetti, J. S. Han, D. W. Cleveland, Inducible, reversible system for the rapid and complete degradation of proteins in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 109, E3350–E3357 (2012).
36
K. Nishimura, T. Fukagawa, H. Takisawa, T. Kakimoto, M. Kanemaki, An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Methods 6, 917–922 (2009).
37
K. Nyquist, A. Martin, Marching to the beat of the ring: Polypeptide translocation by AAA+ proteases. Trends Biochem. Sci. 39, 53–60 (2014).
38
K. C. Liao, J. Mogridge, Expression of Nlrp1b inflammasome components in human fibroblasts confers susceptibility to anthrax lethal toxin. Infect. Immun. 77, 4455–4462 (2009).
39
K. C. Liao, J. Mogridge, Activation of the Nlrp1b inflammasome by reduction of cytosolic ATP. Infect. Immun. 81, 570–579 (2013).
40
T. Maculins, E. Fiskin, S. Bhogaraju, I. Dikic, Bacteria-host relationship: Ubiquitin ligases as weapons of invasion. Cell Res. 26, 499–510 (2016).
41
J. R. Rohde, A. Breitkreutz, A. Chenal, P. J. Sansonetti, C. Parsot, Type III secretion effectors of the IpaH family are E3 ubiquitin ligases. Cell Host Microbe 1, 77–83 (2007).
42
A. U. Singer, J. R. Rohde, R. Lam, T. Skarina, O. Kagan, R. Dileo, N. Y. Chirgadze, M. E. Cuff, A. Joachimiak, M. Tyers, P. J. Sansonetti, C. Parsot, A. Savchenko, Structure of the Shigella T3SS effector IpaH defines a new class of E3 ubiquitin ligases. Nat. Struct. Mol. Biol. 15, 1293–1301 (2008).
43
Y. Zhu, H. Li, L. Hu, J. Wang, Y. Zhou, Z. Pang, L. Liu, F. Shao, Structure of a Shigella effector reveals a new class of ubiquitin ligases. Nat. Struct. Mol. Biol. 15, 1302–1308 (2008).
44
A. K. Hermansson, I. Paciello, M. L. Bernardini, The Orchestra and Its Maestro: Shigella’s Fine-Tuning of the Inflammasome Platforms. Curr. Top. Microbiol. Immunol. 397, 91–115 (2016).
45
C. M. Fernandez-Prada, D. L. Hoover, B. D. Tall, A. B. Hartman, J. Kopelowitz, M. M. Venkatesan, Shigella flexneri IpaH(7.8) facilitates escape of virulent bacteria from the endocytic vacuoles of mouse and human macrophages. Infect. Immun. 68, 3608–3619 (2000).
46
J. Neiman-Zenevich, S. Stuart, M. Abdel-Nour, S. E. Girardin, J. Mogridge, Listeria monocytogenes and Shigella flexneri Activate the NLRP1B Inflammasome. Infect. Immun. 85, e00338-17 (2017).
47
S. Suzuki, H. Mimuro, M. Kim, M. Ogawa, H. Ashida, T. Toyotome, L. Franchi, M. Suzuki, T. Sanada, T. Suzuki, H. Tsutsui, G. Núñez, C. Sasakawa, Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages. Proc. Natl. Acad. Sci. U.S.A. 111, E4254–E4263 (2014).
48
M. C. Okondo, S. D. Rao, C. Y. Taabazuing, A. J. Chui, S. E. Poplawski, D. C. Johnson, D. A. Bachovchin, Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome. Cell Chem. Biol. 25, 262–267.e5 (2018).
49
V. M. Reyes Ruiz, J. Ramirez, N. Naseer, N. M. Palacio, I. J. Siddarthan, B. M. Yan, M. A. Boyer, D. A. Pensinger, J.-D. Sauer, S. Shin, Broad detection of bacterial type III secretion system and flagellin proteins by the human NAIP/NLRC4 inflammasome. Proc. Natl. Acad. Sci. U.S.A. 114, 13242–13247 (2017).
50
S. Suzuki, L. Franchi, Y. He, R. Muñoz-Planillo, H. Mimuro, T. Suzuki, C. Sasakawa, G. Núñez, Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcδ. PLOS Pathog. 10, e1003926 (2014).
51
J. Yang, Y. Zhao, J. Shi, F. Shao, Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proc. Natl. Acad. Sci. U.S.A. 110, 14408–14413 (2013).
52
H. Xu, J. Shi, Z. Yang, F. Shao, N. Dong, The N-end rule E3 ligase UBR2 activates Nlrp1b inflammasomes. bioRxiv 429225 [Preprint]. 27 September 2018.
53
F. Shao, C. Golstein, J. Ade, M. Stoutemyer, J. E. Dixon, R. W. Innes, Cleavage of Arabidopsis PBS1 by a bacterial type III effector. Science 301, 1230–1233 (2003).
54
B. J. DeYoung, D. Qi, S. H. Kim, T. P. Burke, R. W. Innes, Activation of a plant nucleotide binding-leucine rich repeat disease resistance protein by a modified self protein. Cell. Microbiol. 14, 1071–1084 (2012).
55
K. M. Cirelli, G. Gorfu, M. A. Hassan, M. Printz, D. Crown, S. H. Leppla, M. E. Grigg, J. P. J. Saeij, M. Moayeri, Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. PLOS Pathog. 10, e1003927 (2014).
56
S. E. Ewald, J. Chavarria-Smith, J. C. Boothroyd, NLRP1 is an inflammasome sensor for Toxoplasma gondii. Infect. Immun. 82, 460–468 (2014).
57
G. Gorfu, K. M. Cirelli, M. B. Melo, K. Mayer-Barber, D. Crown, B. H. Koller, S. Masters, A. Sher, S. H. Leppla, M. Moayeri, J. P. J. Saeij, M. E. Grigg, Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii. mBio 5, e01117-13 (2014).
58
J. D. Jones, R. E. Vance, J. L. Dangl, Intracellular innate immune surveillance devices in plants and animals. Science 354, aaf6395 (2016).
59
A. M. Schmitz, M. F. Morrison, A. O. Agunwamba, M. L. Nibert, C. F. Lesser, Protein interaction platforms: Visualization of interacting proteins in yeast. Nat. Methods 6, 500–502 (2009).
60
P. Broz, J. von Moltke, J. W. Jones, R. E. Vance, D. M. Monack, Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe 8, 471–483 (2010).
61
K. A. Datsenko, B. L. Wanner, One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl. Acad. Sci. U.S.A. 97, 6640–6645 (2000).
62
A. S. Piro, D. Hernandez, S. Luoma, E. M. Feeley, R. Finethy, A. Yirga, E. M. Frickel, C. F. Lesser, J. Coers, Detection of Cytosolic Shigella flexneri via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility. mBio 8, e01979-17 (2017).
63
K. L. Lightfield, J. Persson, S. W. Brubaker, C. E. Witte, J. von Moltke, E. A. Dunipace, T. Henry, Y.-H. Sun, D. Cado, W. F. Dietrich, D. M. Monack, R. M. Tsolis, R. E. Vance, Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat. Immunol. 9, 1171–1178 (2008).

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Science
Volume 364 | Issue 6435
5 April 2019

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Received: 9 May 2018
Accepted: 5 March 2019
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Acknowledgments

We are grateful to J. Chavarría-Smith for discussions and for laying the experimental foundations for this work. We thank P. R. Beatty and UC Berkeley undergraduates in the MCB150L course for help with generating the 2A12 monoclonal antibody; the Rape laboratory for guidance with ubiquitylation assays; J. Mogridge for the AKR/J Nlrp1b allele construct (21); A. Holland for the AID and TIR1 constructs; the Bachovchin laboratory for the HEK and RAW cell lines and for sharing results before submission; G. Barton, J. Chavarría-Smith, H. Darwin, M. Dorrington, and J. Tenthorey for comments on the manuscript; and members of the Vance and Barton laboratories for discussions. Funding: R.E.V. is an HHMI Investigator and is supported by NIH AI075039 and AI063302. P.S.M. is supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. C.F.L. is a Brit d’Arbeloff MGH Research Scholar and is supported by NIH AI064285. Author contributions: Conceptualization, A.S., P.S.M., and R.E.V.; Methodology, A.S., P.S.M., and R.E.V.; Investigation, A.S., P.S.M., L.G., and E.W.M.; Resources, A.S., P.S.M., L.G., C.F.L., and R.E.V; Writing – Original Draft, A.S., P.S.M., and R.E.V.; Writing – Review & Editing, A.S., P.S.M., C.F.L., and R.E.V.; Visualization, A.S. and P.S.M.; Supervision, A.S., P.S.M., C.F.L., and R.E.V. Competing interests: A patent related to this work has been submitted by R.E.V., A.S., and P.S.M. R.E.V. is a scientific advisory board member for Metchnikoff Therapeutics, Inc. Data and materials availability: All data are available in the main text or the supplementary materials.

Authors

Affiliations

Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, CA, USA.
Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.
Patrick S. Mitchell*
Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, CA, USA.
Lisa Goers
Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, CA, USA.
Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
Division of Immunology and Pathogenesis, Department of Molecular & Cell Biology, and Cancer Research Laboratory, University of California, Berkeley, CA, USA.
Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.

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*
These authors contributed equally to this work.
Corresponding author. Email: [email protected]

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