Negative regulation of CARD11 signaling and lymphoma cell survival by the E3 ubiquitin ligase RNF181

Sarah M. Pedersen, Waipan Chan, Rakhi P. Jattani, de Mauri S. Mackie, Joel L. Pomerantz

Research output: Contribution to journalArticle

Abstract

NF-κB activation downstream of antigen receptor engagement is a highly regulated event required for lymphocyte activation during the adaptive immune response. The pathway is often dysregulated in lymphoma, leading to constitutive NF-κB activity that supports the aberrant proliferation of transformed lymphocytes. To identify novel regulators of antigen receptor signaling to NF-κB, we developed bioluminescence resonance energy transfer-based interaction cloning (BRIC), a screening strategy that can detect protein-protein interactions in live mammalian cells in a high-throughput manner. Using this strategy, we identified the RING finger protein RNF181 as an interactor of CARD11, a key signaling scaffold in the antigen receptor pathway. We present evidence that RNF181 functions as an E3 ubiquitin ligase to inhibit antigen receptor signaling to NF-κB downstream of CARD11. The levels of the obligate signaling protein Bcl10 are reduced by RNF181 even prior to signaling, and Bcl10 can serve as a substrate for RNF181 E3 ligase activity in vitro. Furthermore, RNF181 limits the proliferation of human diffuse large B cell lymphoma cells that depend upon aberrant CARD11 signaling to NF-κB for growth and survival in culture. Our results define a new regulatory checkpoint that can modulate the output of CARD11 signaling to NF-κB in both normal and transformed lymphocytes.

Original languageEnglish (US)
Pages (from-to)794-808
Number of pages15
JournalMolecular and cellular biology
Volume36
Issue number5
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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