* = co-first author, † = corresponding author
NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation
Andreeva L*, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, Wu H.†. Cell 184, 1–16 (2021). PDF
"The NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here, we report that an endogenous, stimulus-responsive form of full-length mouse NLRP3 is a 12- to 16-mer double-ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Read More
Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome
NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, Read More
Dipeptidyl peptidase 9 sets a threshold for CARD8 inﬂammasome formation by sequestering its active C-terminal fragment
Sharif H*, Hollingsworth LR*, Griswold AR*, Hsiao JC, Wang Q, Bachovchin DA†., Wu H† Immunity 54: 1-13 (2021). PDF
Inflammasomes are multiprotein complexes that execute pyroptosis in response to cytosolic danger signals. DPP9 regulates the CARD8 inflammasome by unknown mechanisms. Here, Sharif et al. report cryo-EM structures of CARD8 bound to DPP9 and show that this complex inhibits CARD8 inflammasome activation downstream of the proteasome. Read More
Gasdermin D pore structure reveals preferential release of mature interleukin-1
As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. Read More
DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation
Hollingsworth, L.R.*, Sharif, H.*, Griswold, A.R.*, Fontana P., Mintseris J., Dagbay K.B., Paulo J.A., Gygi S.P., Bachovchin D.A.†, Wu H.† DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature 592, 778–783 (2021). PDF
Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) is an inflammasome sensor that mediates the activation of caspase-1 to induce cytokine maturation and pyroptosis. Gain-of-function mutations of NLRP1 cause severe inflammatory diseases of the skin. NLRP1 contains a function-to-find domain that auto-proteolyses into noncovalently associated subdomains, and proteasomal degradation of the repressive N-terminal fragment of NLRP1 releases its inflammatory C-terminal fragment (NLRP1 CT). Read More
Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes
Hollingsworth LR*., David L*., Li Y*., Griswold AR., Ruan J., Sharif H., Fontana P., Orth-He EL., Fu, T., Bachovchin DA, Wu H.† Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes. Nat Commun 12, 189 (2021). PDF
NLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase-1 activation, cytokine maturation and/or pyroptotic cell death. NLRP1 and CARD8 use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA (conserved in UNC5, PIDD, and ankyrins) subdomain for... Read More
Other Publications (2021)
* = co-first author, † = corresponding author
Vora SM*, Lieberman J, Wu H† (2021). Inflammasome activation at the crux of severe COVID-19. Nat Rev Immunol. 21(11): 694-703.
Magupalli VG†, Fontana P, Wu H† (2021). Ragulator-Rag and ROS TORment gasdermin D pore formation. Trends Immunol. 42: 948-950.
Bittner ZA*, Liu X, Mateo Tortola M, Tapia-Abellán A, Shankar S, Andreeva L, Mangan M, Spalinger M, Kalbacher H, Düwell P, Lovotti M, Bosch K, Dickhöfer S, Marcu A, Stevanović S, Herster F, Cardona Gloria Y, Chang TH, Bork F, Greve CL, Löffler MW, Wolz OO, Schilling NA, Kümmerle-Deschner JB, Wagner S, Delor A, Grimbacher B, Hantschel O, Scharl M, Wu H†, Latz E†, Weber ANR†. (2021) . BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity. J Exp Med. 218(11). doi: 10.1084/jem.20201656.
Fillmore N*, Bell S, Shen C, Nguyen V, La J, Dubreuil M, Strymish J, Brophy M, Mehta G, Wu H†, Lieberman J†, Do N†, Sander C†. (2021). Disulfiram use is associated with lower risk of COVID-19: (2021) A retrospective cohort study. PLoS One. 16(10): e0259061.
Tong AB, Burch JD, McKay D, Bustamante C, Crackower MA, Wu H. Could AlphaFold revolutionize chemical therapeutics?. Nat Struct Mol Biol. 2021 Oct;28(10):771-772. doi: 10.1038/s41594-021-00670-x. PubMed PMID: 34561631.
Gao W, Li Y, Liu X, Wang S, Mei P, Chen Z, Liu K, Li S, Xu XW, Gan J, Wu J, Ji C, Ding C, Liu X, Lai Y, He HH, Lieberman J, Wu H, Chen X, Li J. TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization. Cell Death Differ. 2021 Sep 11;. doi: 10.1038/s41418-021-00867-z. [Epub ahead of print] PubMed PMID: 34511601.
Sun Z*, Yu H*, Zhao J*, Tan T, Pan H, Zhu Y, Chen L, Zhang C, Zhang L, Lei A, Xu Y, Bi X, Huang X, Gao B, Wang L, Correia C, Chen M, Sun Q, Feng Y, Shen L, Wu H, Wang J, Shen X, Daley GQ, Li H, Zhang J (2021). LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells. Protein Cell . doi: 10.1007/s13238-021-00864-5.
Liu X*†, Xia S*, Zhang Z*, Wu H†, Lieberman J† (2021). Channeling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov. 20(5): 384-405.
Shen C*, Vohra M*, Zhang P, Mao X, Figley MD, Zhu J, Sasaki Y, Wu H†, DiAntonio A†, Milbrandt J†. (2021). Multiple domain interfaces mediate SARM1 autoinhibition. Proc Natl Acad Sci USA. 118(4): e2023151118.
Münzer P, Negro R, Fukui S, di Meglio L, Aymonnier K, Chu L, Cherpokova D, Gutch S, Sorvillo N, Shi L, Magupalli VG, Weber ANR, Scharf RE, Waterman CM, Wu H, Wagner DD†. (2021). NLRP3 Inflammasome Assembly in Neutrophils Is Supported by PAD4 and Promotes NETosis Under Sterile Conditions. Front Immunol 12: 683803
Wang L, Sharif H*, Vora SM*, Zheng Y, Wu H† (2021). Structures and functions of the inflammasome engine. J Allergy Clin Immunol 147: 2021-2029
Andreeva L, Wu H (2021). STING condensates on ER limit IFN response. Nat Cell Biol. 23: 299-300