Molecular Mechanisms in Inflammasome Signalling: From NLRP1 to Pyroptosis. Sebastian Hiller
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1 Molecular Mechanisms in Inflammasome Signalling: From NLRP1 to Pyroptosis Sebastian Hiller
2 How do host cells detect pathogens?
3 The inflammasome: a caspase-1 activation platform
4 Inflammasome receptors: modular sensors
5 Latz et al. Nat Rev Immunol 2013, Broz and Dixit Nat Rev Immunol 2016 Canonical Inflammasomes
6 Inflammasomes in health and disease Host defense Genetic disorders Sterile inflammation Bacteria, viruses, fungi, parasites Gain-of-function mutations in NLRP3, NLRC4, PYRIN,.. Gout, Infl. Bowel disease, Asbestosis, Type-II-diabetes,.. Inflammasomes Inflammasomes Beneficial Inflammation (Auto)-inflammatory disease Understanding the basic mechanisms of inflammasome signaling can have an impact on the development of therapies for both infectious as well as (auto)-inflammatory diseases
7 High-resolution methods in structural biology NMR spectroscopy X-ray crystallography cryo-electron microscopy atomic force microscopy
8 Atomic structure of the ASC inflammasome filament
9 Structures of death domains human NLRP1 PYD: human full-length ASC: Hiller et al., Structure 11, 1199 (2003) De Alba, JBC 284, (2009)
10 The ASC-PYD is sufficient to form filaments in cells ATP DNA (AIM2) Scale bars: 10 µm Dick et al., Nat. Comm. (2016)
11 Solid-state NMR spectroscopy of ASC filaments
12 ASC-PYD filament: Sequence-specific resonance assignments Ravotti et al., Biomol. NMR Assign. (2015)
13 Cryo-Electron microscopy of ASC-PYD filament Recorded on Titan Krios with direct electron detector C3 symmetry with 53 right-handed rotation and 14 Å rise
14 Protocol for hybrid structure determination cryo-em solid state NMR alternative protocols: Lange, Sgourakis, Habeck et al.
15 Structure of the mouse ASC PYD filament Sborgi et al., PNAS 112, (2015)
16 Helical filaments in immune signalling MyD88 MAVS CARD Lin et al., Nature 2010; Qiao et al., Mol Cell 2013 Xu et al., elife 2014 solid-state NMR structure: He et al., PNAS 2016 human ASC-PYD mouse (blue) vs. human (green) ASC-PYD Lu et al., Cell 2014
17 Chemical shift differences validate interfaces
18 Structure of the ASC PYD filament
19 Structure-based mutagenesis I N PYD PYD Y59A PYD K21A PYD E80R 0.2 PYD PYD Y59A PYD E80R PYD K21A t [min.]
20 Solid-state NMR: ASC-CARD is flexibly unfolded INEPT INEPT
21 Model for inflammasome assembly
22 Molecular mechanism of a genetic skin disease
23 MSPC and FKLC: Genetic skin diseases MSPC-TN-1 IV:11 MSPC-TN-1 IV:15 MSPC-TN-1 IV:20 MSPC-TN-1 IV:2 MSPC-FR-1 III:2 MSPC-TN-1 IV:20 FKLC-EG-1 V:3 MSPC-RO-1 III:3 MSPC-FR-1 III:2 FKLC-EG-1 V:5 FKLC-EG-1 V:3 MSPC: multiple self-healing palmoplantar carcinoma FKLC: familial keratosis lichenoides chronica Zhong et al. Cell 2016
24 MSPC and FKLC are heritable MSPC-TN-1 I:1 I:2 II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:8 II:9 II:10 II:11 III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:8 III:9 III:10 III:11 III:12 III:13 III:14 III:15 III:16 IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 IV:7 IV:8 IV:9IV:10 IV:11IV:12 IV:13 IV:14 IV:15 IV:16IV:17 IV:18 IV:19 IV:20 IV:21 V:1 V:2 V:3 V:4 V:5 MSPC-RO-1 MSPC-FR-1 FKLC-EG-1 I:1 I:2 I:1 I:2 I:3 I:4 I:1 I:2 II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:1 II:2 II:1 II:2 II:3 II:4 III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:8 III:9 III:10 III:11 III:12 III:13 III:1 III:2 III:1 III:2 III:3 III:4 III:5 III:6 III:8 IV:1 IV:1 IV:2 IV:3 IV:4 IV:5 IV:6 V:1 V:2 V:3 V:4 V:5 V:6 V:7 MSPC: multiple self-healing palmoplantar carcinoma FKLC: familial keratosis lichenoides chronica
25 MSPC and FKLC locate to NLRP1 Chr.17p13.2: 5,417,438-5,487,832 NLRP1 Exon NLRP1 1 PYD NACHT LRR FIIND CARD 1474 p.f787_r843del FKLC-EG-1 Human 1-MAGGAWGRLACYLEFLKKEELKEFQLLLANKAHSRSSSGETPAQPEKTSGMEVASYLVAQYGEQRAWDLALHTWEQMGLRSLCAQAQEGAGH RA W QM G -92 Chimpanzee 1-MAGGAWGRLACYLEFLKKEELKEFQLLLANKAHSRSSSGETPAQPEKTSGMEVASYLVAQYGEQRAWDLALHTWEQMGLRSLCTQAQEGAGH RA W QM G -92 Macaque 1-MAGGAWGRLACYLELLKKEELKEFQLLFASKVHSSGSSGETPARPEKTSGMEVASYLVAQYGEQRAWDLALRTWEQMGLWSLCTQAREGAGY VA RA W QM G -92 Marmoset 1-MAGGAWGRLACYLELLEKEELKKFQFLLTNKVHSRGSSGETPAQPEKTSGMQVASHLVAQYGEQQAWDLAIHIWEQMGLRSLCAQAQEEAGH VA QA W QM G -92 Gibbon 1-MAGGAWGRLACYLEFLKKEELKEFQLLLANKAHSRSSSGETPTQPEKTSGMEVASYLVAQYGEQRAWDLALHTWEQMGLRSLCAQAQEGAGH RA W QM G -92 Horse 1-MAGGAELQWPWYLESREKKEPKEFQLRLPD-AHSRHSPGETVAQV-EASGPEVASRLVALYGQRQAWDLALLTQRRMDLSRVSIQAHREAAS V QA W RM D -90 Dog 1-MACRVQWQLAWYLEMMGKEELKEFQLRLLEQQFWGDPPHALRAQLGKARGLEVASRLVAQYGEQQAWVLALRTWEEMGLSRLCAQSRAEAGL VA QA W EMG -92 conservation **. : *** *:* *:**: :.. :: :: * :*** *****:::** **:.. * * :. *:: *. p.a54t MSPC-TN-1 p.a66v MSPC-RO-1 p.m77t MSPC-FR-1 MSPC: multiple self-healing palmoplantar carcinoma FKLC: familial keratosis lichenoides chronica
26 NLRP1 is the predominant NLR in human skin **** NLRP1 NLRP3 RNAscope: dapb RNAscope: NLRP1 FKPM AIM2 NLRC4 MEFV hair-bearing skin IHC: no primary Ab IHC: NLRP1 Skin Bone marrow Spleen NLRP1 NLRP3 MEFV AIM2 NLRC4 fibroblasts melanocytes keratinocytes PBMCs Primary human cells Inflammasome sensors CASP1 ASC IL1B IL18 KRT14 GAPDH fibroblasts melanocytes keratinocytes PBMCs Inflammasome effectors and substrates plantar skin IHC: no primary Ab IHC: NLRP1 50 μm
27 MSPC mutations increase NLRP1 activity 293T-ASC-GFP 80 ** DAPI ASC-GFP DAPI ASC-GFP 60 NLRP1 mutants (this study) vector NLRP1 WT NLRP1 A54T NLRP1 M77T NLRP1 A66V NLRP1 F787_R843del 20 μm % cells with ASC specks ** Vector WT R8H n.s NLRP1 SNPs (1000 Genome) N30D A32V R35G S36R T41A P42T A43T T48M S49G S55L E63K Q64H A84T A86T E88K A54T M77T A66V F787_R843del
28 MSPC mutations unfold PYD domain of NLRP1 NLRP1 PYD domain Unfolded PYD leads to Nlrp1 activation Nlrp1 PYD plays inhibitory function Zhong et al. Cell 2016
29 NLRP1 signals via its CARD domain Zhong et al. Cell 2016
30 Human NLRP1: Model of autoinhibition Zhong et al. Cell 2016
31 Molecular mechanism of pyroptotic cell death
32 Gasdermin-D is essential for pyroptosis induction GSDMD is required for both caspase-1- and caspase-11-induced pyroptosis Caspase-mediated processing of GSDMD into a N- and C-terminal fragment is essential The N-terminal domain harbors the cytotoxic activity Salmonella infection (NLRC4 inflammasome) Kayagaki et al. Nature (2015), Shi et al. Nature (2015)
33 The GSDMD protein family N 30 kda C 53 kda protein, consisting of two domains (GSDMD Nterm and GSDMD Cterm ) Expressed in the gastrointestinal tract and the dermis Belongs to the ill-characterized gasdermin protein family (6 human / 10 murine members) All members share a similar N-terminal domain GSDMD CTERM mouse human mouse GSDMA3 Ding et al. Nature (2016)
34 GSDMD Nterm targets cellular membranes GSDMD VDAC (mitochondria) HDAC (nucleus) Na+K+ ATPase (plasma membrane) GAPDH (cytosol) Subcellular fractionation of macrophages left uninfected (NS) or infected with S. typhimurium Sborgi et al. EMBO J. 2016
35 GSDMD Nterm targets liposomes in vitro GSDMD Nterm targets liposomes after in vitro cleavage GSDMD FL GSDMD Nterm GSDMD Cterm Sborgi et al. EMBO J. 2016
36 GSDMD Nterm lyses liposomes in vitro GSDMD Nterm induces dye release from liposomes (6-carboxifluorescein, self-quenching) nm GSDMD + 5 nm Casp1 Sborgi et al. EMBO J. 2016
37 Cryo-Electron Microscopy of GSDMD pores in liposomes untreated GSDMD GSDMD + Casp1 (0 ) GSDMD + Casp1 (30 ) GSDMD + Casp1 (60 ) Sborgi et al. EMBO J. 2016
38 Atomic force microscopy analysis of GSDMD pores Pore formation by GSDMD Nterm is the effector mechanism of pyroptosis Sborgi et al. EMBO J. 2016
39 Mechanism of pyroptotic cell death
40 Acknowledgements Lorenzo Sborgi Adam Mazur Joka Pipercevic Petr Broz Mathias Dick Sebastian Rühl Henning Stahlberg Venkat Dandey Timm Maier Daniel Müller Estefania Mulvihill Beat Meier Francesco Ravotti Anja Böckmann Bruno Reversade Franklin Zhong Ed Egelman Chris Farady
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