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2022 Publications

* = co-first author, † = corresponding author
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 Cryo-EM structures of the active NLRP3 inflammasome disk 

Xiao L*, Magupalli VG, Wu H †  Nature (2022) 613 (7944) 595-600.. PDF

Inflammasomes are cytosolic innate immune complexes that activate caspase-1 upon detection of pathogenic and endogenous dangers1-5, and NLRP3 is an inflammasome sensor of membrane damage highly important in inducing inflammation2,6,7. Here we report cryo-EM structures of disk-shaped active NLRP3 oligomers in complex with ATP𝛾S, the centrosomal kinase NEK7, and the adaptor protein ASC which recruits caspase-1. In these NLRP3-NEK7-ASC complexes, the central NACHT domain of NLRP3 assumes an ATP-bound conformation in which two of its subdomains rotate by ~85 ° relative to the ADP-bound inactive conformation8-12. ... Read More

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Structural principles of B cell antigen receptor assembly 

Dong Y*, Pi X*, Bartels-Burgahn F, Saltukoglu D, Liang Z, Yang J, Alt FW, Reth M, Wu H †  Nature (2022) 612(7938):156-161. PDF

The B cell antigen receptor (BCR) is composed of a membrane-bound class M, D, G, E or A immunoglobulin for antigen recognition1–3 and a disulfde-linked Igα (also known as CD79A) and Igβ (also known as CD79B) heterodimer (Igα/β) that functions as the signalling entity through intracellular immunoreceptor tyrosine-based activation motifs (ITAMs)4,5 . The organizing principle of the BCR remains unknown.... Read More

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Structure of cytoplasmic ring of nuclear pore complex by integrative cryo-EM and AlphaFold

Fontana P*, Dong Y*, Pi X*, Tong AB, Hecksel CW, Wang L, Fu TM, Bustamante C, Wu H †. Science. (2022) Jun 10;376(6598):eabm9326. doi: 10.1126/science.abm9326.  PDF

The nuclear pore complex (NPC) is the molecular conduit in the nuclear membrane of eukaryotic cells that regulates import and export of biomolecules between the nucleus and the cytosol, with vertebrate NPCs ~110 to 125 MDa in molecular mass and ~120 nm in diameter. NPCs are organized into four main rings: the cytoplasmic ring (CR) at the cytosolic side,  Read More

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BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL

Xia M*, David L, Teater M, Gutierrez J, Wang X, Meydan C, Lytle A, Slack GW, Scott DW, Morin RD, Onder O, Elenitoba-Johnson KSJ, Zamponi N, Cerchietti L, Lu T, Philippar U, Fontan L, Wu H†, Melnick AM†. Cancer Discov. (2022) Aug 5;12(8):1922-1941. doi: 10.1158/2159-8290.CD-21-1566. PDF

Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Read More

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pH regulates potassium conductance and drives a constitutive proton current in human TMEM175

Zheng W*, Shen C, Wang L, Rawson S, Xie WJ, Nist-Lund C, Wu J, Shen Z, Xia S, Holt JR, Wu † Fu TM.. Sci Adv. (2022) Mar 25;8(12):eabm1568. doi: 10.1126/sciadv.abm1568. PDF

Human TMEM175, a noncanonical potassium (K+) channel in endolysosomes, contributes to their pH stability and is implicated in the pathogenesis of Parkinson's disease (PD). Structurally, the TMEM175 family exhibits an architecture distinct from canonical potassium channels, as it lacks the typical TVGYG selectivity filter.  Read More

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Targeting stem-loop 1 of the SARS-CoV-2 5' UTR to suppress viral translation and Nsp1 evasion

Vora SM*, Fontana P, Mao T, Leger V, Zhang Y, Fu TM, Lieberman J, Gehrke L, Shi M, Wang L, Iwasaki A, Wu H..†. Proc Natl Acad Sci U S A.  (2022) Mar 1;119(9). doi: 10.1073/pnas.2117198119.. PDF

SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis Read More


Electrostatic influence on IL-1 transport through the GSDMD pore

Xie WJ*, Xia S, Warshel A, Wu H.†. Proc Natl Acad Sci U S A. (2022 ) Feb 8;119(6). doi10.1073/pnas.2120287119. PDF

A variety of signals, including inflammasome activation, trigger the formation of large transmembrane pores by gasdermin D (GSDMD). There are primarily two functions of the GSDMD pore, to drive lytic cell death, known as pyroptosis, and to permit the release of leaderless interleukin-1 (IL-1) family cytokines, a process that does not require pyroptosis. We are interested in the mechanism by which the GSDMD pore channels IL-1 release from living cells. Recent studies revealed that electrostatic interaction, in addition to cargo size, plays a critical role in GSDMD-dependent protein release. Read More

Other Publications (2022)
* = co-first author, † = corresponding author

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.  (2022) LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells. Protein Cell. 13(7):490-512.

Junqueira C, Crespo Â, Ranjbar S, de Lacerda LB, Lewandrowski M, Ingber J, Parry B, Ravid S, Clark S, Schrimpf MR, Ho F, Beakes C, Margolin J, Russell N, Kays K, Boucau J, Das Adhikari U, Vora SM, Leger V, Gehrke L, Henderson LA, Janssen E, Kwon D, Sander C, Abraham J, Goldberg MB, Wu H, Mehta G, Bell S, Goldfeld AE, Filbin MR, Lieberman J. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature. 2022 Jun;606(7914):576-584.


Meza-Sosa KF, Miao R, Navarro F, Zhang Z, Zhang Y, Hu JJ, Hartford CCR, Li XL, Pedraza-Alva G, Pérez-Martínez L, Lal A, Wu H, Lieberman J. SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage. Mol Cell. 2022 Feb 17;82(4):785-802

Deng W, Bai Y, Deng F, Pan Y, Mei S, Zheng Z, Min R, Wu Z, Li W, Miao R, Zhang Z, Kupper TS, Lieberman J, Liu X. 2022 ) Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis.  Nature. doi: 10.1038/s41586-021-04384-4. 

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.  2022 )  TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization. Cell Death Differ. Feb;29(2):439-450. 

Wang L, Crackower MA, Wu H. 2022 )  Advances toward structure-based drug discovery for inflammasome targets. J Exp Med. Jan 3;219(1). doi: 10.1084/jem.20211147. 

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