Intramolecular Interactions and Regulation of Cofactor Binding by the Four Repressive Elements in the Caspase Recruitment Domain-containing Protein 11 (CARD11) Inhibitory Domain.

The Journal of Biological Chemistry
Rakhi P JattaniJoel L Pomerantz

Abstract

The CARD11 signaling scaffold transmits signaling between antigen receptors on B and T lymphocytes and the transcription factor NF-κB during the adaptive immune response. CARD11 activity is controlled by an inhibitory domain (ID), which participates in intramolecular interactions and prevents cofactor binding prior to receptor triggering. Oncogenic CARD11 mutations associated with the activated B cell-like subtype of diffuse large B cell lymphoma somehow perturb ID-mediated autoinhibition to confer CARD11 with the dysregulated spontaneous signaling to NF-κB that is required for the proliferation and survival of the lymphoma. Here, we investigate how the four repressive elements (REs) we have discovered in the CARD11 ID function to inhibit CARD11 activity with cooperativity and redundancy. We find that each RE contributes to the maintenance of the closed inactive state of CARD11 that predominates in the absence of receptor engagement. Each RE also contributes to the prevention of Bcl10 binding in the basal unstimulated state. RE1, RE2, and RE3 participate in intramolecular interactions with other CARD11 domains and share domain targets for binding. Remarkably, diffuse large B cell lymphoma-associated gain-of-function mutations i...Continue Reading

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Citations

Jun 20, 2017·Nature Genetics·Chi A MaJoshua D Milner
Feb 24, 2018·Frontiers in Immunology·Swadhinya ArjunarajaAndrew L Snow
Nov 24, 2018·Nature Reviews. Immunology·Jürgen Ruland, Lara Hartjes
Jul 13, 2019·Nature Communications·Michael J HollidayWayne J Fairbrother
Jul 16, 2016·Biological Chemistry·Isabel Meininger, Daniel Krappmann
Oct 5, 2018·Frontiers in Immunology·Jacquelyn R BedsaulJoel L Pomerantz
Oct 9, 2019·Cellular & Molecular Immunology·Dandan YangXin Lin
Aug 9, 2019·The Journal of Biological Chemistry·Zhaoquan WangJoel L Pomerantz
May 8, 2019·The Journal of Allergy and Clinical Immunology·Henry Y LuStuart E Turvey
Aug 4, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Shelby M HutchersonJoel L Pomerantz

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