2021 Publications

Highlights
* = co-first author, † = corresponding author

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

Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y, Vora SM, Wang L, Fu T-M, Jacobson MP, Greka A, Lieberman J, Ruan J,, Wu H†. Nature 593: 607-611 (2021) PDF

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. Inflammasome activation at the crux of severe COVID-19. Nat Rev Immunol. 2021 Aug 9;. doi: 10.1038/s41577-021-00588-x. [Epub ahead of print] Review. PubMed PMID: 34373622; PubMed Central PMCID: PMC8351223.

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. LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells. Protein Cell. 2021 Jul 31;. doi: 10.1007/s13238-021-00864-5. [Epub ahead of print] PubMed PMID: 34331666.

Liu X*,  Xia S*, Zhang Z*,  Wu H, Lieberman J. (2021). Channeling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov.

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).

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