Related Experiment Video
Updated: May 18, 2026
08:49
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Protein Homeostasis Screen Identifies CK2 Inhibition as a Driver of CARD9 Depletion
Aya M Kelly1, Leidy C Merselis2, Benjamin Causton2
1Lead Discovery and Optimization, Discovery and Development Sciences, Bristol Myers Squibb, 250 Water St., Cambridge, Massachusetts 02141, United States.
ACS Chemical Biology
|May 16, 2026
Summary
Researchers found that inhibiting casein kinase 2 (CK2) depletes CARD9 protein, offering a new way to target this protein for autoimmune diseases. This discovery provides a potential therapeutic strategy for conditions like inflammatory bowel disease.
Area of Science:
- Immunology
- Molecular Biology
- Drug Discovery
Background:
- Card9 (caspase recruitment domain-containing protein 9) is a validated target for autoimmune diseases.
- Elevated Card9 expression is linked to increased disease risk, while lower expression offers protection.
- A rare Card9 loss-of-function variant (Card9Δ11) protects against inflammatory bowel disease.
Purpose of the Study:
- To identify novel therapeutic strategies targeting Card9, previously considered undruggable.
- To explore the role of protein homeostasis in regulating Card9 levels.
- To investigate the mechanism by which Card9 is regulated and its potential therapeutic implications.
Main Methods:
- Protein homeostasis screening to identify regulators of Card9.
- Biochemical assays to study the interaction between Card9 and casein kinase 2 (CK2).
- In vivo studies using a murine peritonitis model to assess therapeutic efficacy.
Main Results:
- Inhibition of CK2 leads to the depletion of Card9 protein in various cell types.
- CK2 directly phosphorylates Card9, promoting its destabilization.
- The Card9Δ11 variant shows reduced interaction with CK2, conferring resistance to CK2-mediated stabilization.
- CK2 inhibition effectively reduced Card9 levels in a mouse model of peritonitis.
Conclusions:
- CK2 inhibition represents a novel and unconventional approach to target Card9 for autoimmune diseases.
- This mechanism of Card9 depletion by CK2 inhibitors may explain the protective effects of the Card9Δ11 allele.
- The findings expand the understanding of kinase inhibitor functions and offer a new strategy for intractable targets.
Related Concept Videos
02:34Inhibition of Cdk Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
02:34Inhibition of CDK Activity
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...