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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, Massachusetts02141, United States.

ACS Chemical Biology
|May 16, 2026
PubMed

Insights

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.

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