Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

Mao, Liming; Kitani, Atsushi; Similuk, Morgan; Oler, Andrew J.; Albenberg, Lindsey; Kelsen, Judith R.; Aktay, Atiye; Quezado, Martha; Yao, Michael; Montgomery-Recht, Kim; Fuss, Ivan J.; Strober, Warren

doi:10.1172/jci98642

Cited by 87 publications

(83 citation statements)

References 51 publications

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“…Our work also identified a second FIIND-containing inflammasome regulator, CARD8 as a DPP9-binding partner. Although the role of CARD8 in human inflammasome regulation remains to be clarified, germline mutations in CARD8 have been shown to cause a Mendelian autoinflammatory syndrome via the NLRP3 inflammasome (38). Because CARD8 does not exist in rodents, it is very likely that DPP9 has broader functions in the human innate immune system than previous mouse experiments have demonstrated through its combined action on human NLRP1 and CARD8 (Fig.…”

Section: Dpp9 Represses Human Nlrp1 Inflammasomementioning

confidence: 97%

Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

Zhong

Robinson

Teo

et al. 2018

Journal of Biological Chemistry

205

249

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The inflammasome is a critical molecular complex that activates interleukin-1 driven inflammation in response to pathogen-and danger-associated signals. Germline mutations in the inflammasome sensor NLRP1 cause Mendelian systemic autoimmunity and skin cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP8/9 inhibition via small molecule drugs and CRISPR/Cas9-mediated genetic deletion specifically activate the human NLRP1 inflammasome, leading to ASC speck formation, pyroptotic cell death, and secretion of cleaved interleukin-1␤. Mechanistically, DPP9 interacts with a unique autoproteolytic domain (Function to Find Domain (FIIND)) found in NLRP1 and CARD8. This scaffolding function of DPP9 and its

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Section: Dpp9 Represses Human Nlrp1 Inflammasomementioning

confidence: 97%

Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

Zhong

Robinson

Teo

et al. 2018

Journal of Biological Chemistry

205

249

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show abstract

“…Nlrp3 inflammasome signaling is postulated to play a role in a growing array of inflammatory diseases, ranging from IBD, 79 rheumatic diseases, 80 and pancreatitis 81 to the neurodegenerative disorder Alzheimer's disease 82 . This renders it a promising therapeutic target 25 .…”

Section: Nod‐like Receptor Familymentioning

confidence: 99%

The microbiome and cytosolic innate immune receptors

Liwinski

Zheng

Elinav

2020

Immunological Reviews

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The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune‐mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host‐environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide‐binding domain, leucine‐rich repeat‐containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)–like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid‐inducible gene‐I (RIG‐I)–like receptors (RLRs), cyclic GMP‐AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host‐microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.

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“…One mechanism of regulation of NLRP3 inflammasome activation involves the phosphorylation of NLRP3 that is manifest in the complex array of phosphorylation and/or dephosphorylation events that serve as known checkpoints of inflammasome activation (6). Another mechanism of regulation involves the binding of molecules, such as NIMA related kinase 7 (NEK7) (7,8) or caspase recruitment domain family member 8 (CARD8) (9), which have the capacity to modify NLRP3 function. In the present study, we investigated the regulation of the NLRP3 inflammasome by Bruton tyrosine kinase (BTK), a molecule that falls into both categories of NLRP3 inflammasome activation modifiers in that it binds NLRP3 and affects NLRP3 phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis

Mao

Kitani

Hiejima

et al. 2020

Journal of Clinical Investigation

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Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

Cited by 87 publications

References 51 publications

Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

The microbiome and cytosolic innate immune receptors

Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis

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