Article
Chemistry, Medicinal
Qifeng Chen, Alvin Wang, Dominic J. Covelli, Abir Bhattacharjee, Qinghui Wang, Elizabeth L. Orth-He, Sahana D. Rao, Hsin-Che Huang, Daniel P. Ball, Jeffrey C. Hsiao, Daniel A. Bachovchin
Summary: Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. A recent study found that NLRP1 and CARD8 inflammasomes, which detect danger signals, can be selectively activated by a dual inhibitor called CQ31. Further studies led to the development of a more effective inhibitor, CQ80, which induces CARD8 inflammasome activation. CQ80 is expected to be a valuable tool for studying the biology and therapeutic potential of selective CARD8 inflammasome activation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Sahana D. Rao, Qifeng Chen, Qinghui Wang, Elizabeth L. Orth-He, Michelle Saoi, Andrew R. Griswold, Abir Bhattacharjee, Daniel P. Ball, Hsin-Che Huang, Ashley J. Chuff, Dominic J. Covelli, Shaochen You, Justin R. Cross, Daniel A. Bachovchin
Summary: Researchers have identified a small molecule called CQ31 that selectively activates the CARD8 inflammasome. CQ31 inhibits the activities of prolidase and Xaa-Pro aminopeptidase 1, leading to an increase in proline-containing peptides that activate CARD8 without affecting NLRP1. This study is important for understanding the biology of CARD8.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Biology
Jessie Kulsuptrakul, Elizabeth A. Turcotte, Michael Emerman, Patrick S. Mitchell
Summary: During HIV-1 infection, CARD8 is activated by HIV protease through site-specific cleavage, leading to pyroptotic cell death and release of pro-inflammatory cytokines. The cleavage site in human CARD8 emerged after the divergence of chimpanzees and humans, suggesting that simian immunodeficiency virus in chimpanzees was already capable of activating the CARD8 inflammasome in humans prior to cross-species transmission.
Article
Multidisciplinary Sciences
Qiankun Wang, Hongbo Gao, Kolin M. Clark, Christian Shema Mugisha, Keanu Davis, Jack P. Tang, Gray H. Harlan, Carl J. DeSelm, Rachel M. Presti, Sebla B. Kutluay, Liang Shan
Summary: HIV-1's rapid evolution and high mutation rates enable it to evade the host immune system, but intervention targeting the protease activity with the inflammasome sensor CARD8 has shown promise in clearing latent HIV-1 infection.
Article
Multidisciplinary Sciences
Qin Gong, Kim Robinson, Chenrui Xu, Phuong Thao Huynh, Kelvin Han Chung Chong, Eddie Yong Jun Tan, Jiawen Zhang, Zhao Zhi Boo, Daniel Eng Thiam Teo, Kenneth Lay, Yaming Zhang, John Soon Yew Lim, Wah Ing Goh, Graham Wright, Franklin L. Zhong, Bruno Reversade, Bin Wu
Summary: NLRP1 and CARD8 are two recently characterized sensor proteins for the human inflammasome complex. The cryo-EM CARD filament structures of the NLRP1 and CARD8 activating domains reveal how NLRP1 and CARD8 discriminate between ASC and pro-caspase-1. The authors propose a two-step model for NLRP1 activation.
NATURE COMMUNICATIONS
(2021)
Article
Immunology
Zhihao Xu, Shasha Deng, Yuluo Huang, Yunru Yang, Liangqi Sun, Hanyuan Liu, Dan Zhao, Weihong Zeng, Xueying Yin, Peiyi Zheng, Yingying Wang, Muziying Liu, Weidong Zhao, Tsan Sam Xiao, Ying Zhou, Tengchuan Jin
Summary: This study elucidates the regulation of NLRP1 inflammasome activation by CARD8 and provides insights into the assembly mechanisms of CARD-containing inflammasomes.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Rhea Nadkarni, Wern Cui Chu, Cheryl Q. E. Lee, Yasir Mohamud, Lynn Yap, Gee Ann Toh, Sheryl Beh, Radiance Lim, Yiyun Michelle Fan, Yizhuo Lyanne Zhang, Kim Robinson, Karl Tryggvason, Honglin Luo, Franklin Zhong, Lena Ho
Summary: Nadkarni et al. demonstrate the crucial role of CARD8 inflammasome in endothelial cell intrinsic immunity, regulating the propagation and inflammation response of CVB3. Additionally, they found that CARD8 is activated in ECs through viral protease cleavage, and contributes to the regulation of CVB3 infection.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Immunology
Humayun Sharif, L. Robert Hollingsworth, Andrew R. Griswold, Jeffrey C. Hsiao, Qinghui Wang, Daniel A. Bachovchin, Hao Wu
Summary: CARD8 senses danger signals and forms an inflammasome, which can be activated by DPP8/9 inhibitors promoting CARD8 NT degradation and weakening ternary complex stability.
Article
Biochemistry & Molecular Biology
Brian V. V. Tsu, Rimjhim Agarwal, Nandan S. S. Gokhale, Jessie Kulsuptrakul, Andrew P. P. Ryan, Elizabeth J. J. Fay, Lennice K. K. Castro, Christopher Beierschmitt, Christina Yap, Elizabeth A. A. Turcotte, Sofia E. E. Delgado-Rodriguez, Russell E. E. Vance, Jennifer L. L. Hyde, Ram Savan, Patrick S. S. Mitchell, Matthew D. D. Daugherty
Summary: Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. The 3CL protease (3CL(pro)) encoded by diverse coronaviruses cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology.
Article
Biology
Brian Ritchey, Qimin Hai, Juying Han, John Barnard, Jonathan D. Smith
Summary: The study identified a single-nucleotide polymorphism in the 3' untranslated region of the Pycard gene in DBA/2 and AKR mice, leading to differences in inflammasome activity. Using CRISPR/Cas9 gene editing, the researchers changed the Pycard gene from the DBA/2 to the AKR allele, resulting in reduced inflammasome activity.
Article
Biology
Jaideep Mahendra, Abirami Nayaki Rao, Little Mahendra, Hytham N. Fageeh, Hammam Ibrahim Fageeh, Thodur Madapusi Balaji, Saranya Varadarajan, Raghunathan Jagannathan, Deepak Mehta, Venkata V. Suresh, A. Thirumal Raj, Shankargouda Patil
Summary: This study aimed to evaluate the relationship between certain biomolecules and gum and heart disease. The findings indicated that patients with severe gum disease and poor oral health may develop heart problems in the future, highlighting the importance of early prevention of oral diseases and gum ailments to reduce the risk of future heart diseases.
Article
Infectious Diseases
Hector David Graterol Sequera, Josue Lacerda de Souza, Jose do Espirito Santo, Lener Santos da Silva, Suzana Kanawati Pinheiro, Herllon Karllos Athaydes Kerr, Mara Lucia Gomes de Souza, Marcus Vinitius de Farias Guerra, Tirza Gabrielle Ramos de Mesquita, Rajendranath Ramasawmy
Summary: Nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein family (NLR) are intracellular pathogen recognition receptors mediating innate immunity. The study investigated the role of single nucleotide variants in the CARD8 gene in the development of cutaneous leishmaniasis caused by Leishmania guyanensis in individuals from an endemic area of leishmaniasis.
PLOS NEGLECTED TROPICAL DISEASES
(2023)
Article
Biology
Wei-Ting Hung, Yi-Ming Chen, Shuen-Iu Hung, Hsin-Hua Chen, Ning-Rong Gung, Chia-Wei Hsieh, Kuo-Tung Tang, Der-Yuan Chen
Summary: A study found that the SNP rs11672725 of the CARD8 gene is significantly associated with AOSD susceptibility, with patients carrying the CC genotype and C allele having lower CARD8 levels and being predisposed to a systemic pattern of disease outcome with elevated inflammasome signaling expression.
Article
Cell Biology
Ying Ye, Qinjin Dai, Hongbo Qi
Summary: This study identified pyroptosis-related genes in ovarian cancer (OC) that may play important roles in tumor immunity and can be used to predict the prognosis of OCs. By dividing OC cases into subtypes based on the expression of these genes, different risk groups were identified with significant differences in survival possibilities. Additionally, immune-related genes were found to be enriched in high-risk groups, indicating a decreased immune status in these patients.
CELL DEATH DISCOVERY
(2021)
Article
Biochemistry & Molecular Biology
Antonella La Russa, Danilo Lofaro, Alberto Montesanto, Daniele La Russa, Gianluigi Zaza, Simona Granata, Michele Di Dio, Raffaele Serra, Michele Andreucci, Renzo Bonofiglio, Anna Perri
Summary: In this study, the association of functional variants of NLRP3 pathway-related genes (NLRP3-rs10754558, CARD8-rs2043211) with CKD susceptibility was investigated for the first time. Logistic regression analyses revealed significantly higher frequencies of the G allele of NLRP3 variant (67.3%) and the T allele of CARD8 variant (70.8%) among cases compared to controls (35.9% and 31.2%, respectively). The results suggest that NLRP3 rs10754558 and CARD8 rs2043211 variants may be associated with susceptibility to CKD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
L. Robert Hollingsworth, Liron David, Yang Li, Andrew R. Griswold, Jianbin Ruan, Humayun Sharif, Pietro Fontana, Elizabeth L. Orth-He, Tian-Min Fu, Daniel A. Bachovchin, Hao Wu
Summary: NLRP1 and CARD8 form supramolecular signaling complexes called canonical inflammasomes upon activation, leading to caspase-1 activation, cytokine maturation, and/or pyroptotic cell death. Their C-terminal fragments containing a CARD and the UPA subdomain facilitate self-oligomerization, recruiting the inflammasome adaptor ASC or caspase-1 for further signaling.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
L. Robert Hollingsworth, Humayun Sharif, Andrew R. Griswold, Pietro Fontana, Julian Mintseris, Kevin B. Dagbay, Joao A. Paulo, Steven P. Gygi, Daniel A. Bachovchin, Hao Wu
Summary: NLRP1 is an inflammasome sensor that mediates caspase-1 activation, and its function is regulated by DPP8/DPP9, with VbP disrupting the NLRP1-DPP9 interaction to accelerate inflammasome activation.
Article
Biochemistry & Molecular Biology
Sahana D. Rao, Qifeng Chen, Qinghui Wang, Elizabeth L. Orth-He, Michelle Saoi, Andrew R. Griswold, Abir Bhattacharjee, Daniel P. Ball, Hsin-Che Huang, Ashley J. Chuff, Dominic J. Covelli, Shaochen You, Justin R. Cross, Daniel A. Bachovchin
Summary: Researchers have identified a small molecule called CQ31 that selectively activates the CARD8 inflammasome. CQ31 inhibits the activities of prolidase and Xaa-Pro aminopeptidase 1, leading to an increase in proline-containing peptides that activate CARD8 without affecting NLRP1. This study is important for understanding the biology of CARD8.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jeffrey C. Hsiao, Atara R. Neugroschl, Ashley J. Chui, Cornelius Y. Taabazuing, Andrew R. Griswold, Qinghui Wang, Hsin-Che Huang, Elizabeth L. Orth-He, Daniel P. Ball, Giorgos Hiotis, Daniel A. Bachovchin
Summary: CARD8, a pattern-recognition receptor, is involved in the activation of the inflammasome. The degradation of CARD8 by the 20S proteasome plays a crucial role in the control of inflammasome activation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Immunology
Andrew R. Griswold, Julia Klein, Neville Dusaj, Jeff Zhu, Allegra Keeler, Erika L. Abramson, Dana Gurvitch
Summary: The COVID-19 pandemic has disrupted education but also led to innovative service-learning approaches in response to pandemic-related challenges. This study introduces a service-learning vaccination program that trained medical students to administer COVID-19 vaccines in underserved communities. The program was shown to teach clinical skills and provide a meaningful learning experience.
Article
Chemistry, Medicinal
Qifeng Chen, Alvin Wang, Dominic J. Covelli, Abir Bhattacharjee, Qinghui Wang, Elizabeth L. Orth-He, Sahana D. Rao, Hsin-Che Huang, Daniel P. Ball, Jeffrey C. Hsiao, Daniel A. Bachovchin
Summary: Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. A recent study found that NLRP1 and CARD8 inflammasomes, which detect danger signals, can be selectively activated by a dual inhibitor called CQ31. Further studies led to the development of a more effective inhibitor, CQ80, which induces CARD8 inflammasome activation. CQ80 is expected to be a valuable tool for studying the biology and therapeutic potential of selective CARD8 inflammasome activation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Cell Biology
Elizabeth L. Orth-He, Hsin-Che Huang, Sahana D. Rao, Qinghui Wang, Qifeng Chen, Claire M. O'Mara, Ashley J. Chui, Michelle Saoi, Andrew R. Griswold, Abir Bhattacharjee, Daniel P. Ball, Justin R. Cross, Daniel A. Bachovchin
Summary: NLRP1 and CARD8 are pattern-recognition receptors that detect danger signals and form inflammasomes. The N-terminal fragments of these receptors can be degraded through various agents that interfere with protein folding, but the released C-terminal fragments are sequestered by DPP9. To trigger inflammasome formation, DPP9-binding ligands are required to disrupt the complexes and allow the C-terminal fragments to oligomerize.
Article
Immunology
Daniel P. Ball, Lydia P. Tsamouri, Alvin E. Wang, Hsin-Che Huang, Charles D. Warren, Qinghui Wang, Isabelle H. Edmondson, Andrew R. Griswold, Sahana D. Rao, Darren C. Johnson, Daniel A. Bachoychin
Summary: This study discovered that oxidized thioredoxin-1 (TRX1) binds to the NACHT-LRR region of NLRP1, forming a stable complex that restrains inflammasome activation. Reductive stress is identified as a danger signal that activates the NLRP1 inflammasome by eliminating oxidized TRX1 and interrupting the TRX1-NLRP1 interaction.
SCIENCE IMMUNOLOGY
(2022)