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Gain-of-function mutations in CARD11 promote enhanced aggregation and idiosyncratic signalosome assembly.

Cell Immunol. 2020 Jul;353:104129. Epub 2020 May 14
Jeffrey R Stinson 1 , Batsukh Dorjbal 2 , Dennis P McDaniel 3 , Liron David 4 , Hao Wu 5 , Andrew L Snow 6
Jeffrey R Stinson 1 , Batsukh Dorjbal 2 , Dennis P McDaniel 3 , Liron David 4 , Hao Wu 5 , Andrew L Snow 6
+ et al

[No authors listed]

Author information
  • 1 Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of Health Sciences, Bethesda, MD, United States. Electronic address: jeffrey.stinson@nist.gov.
  • 2 Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
  • 3 Biomedical Instrumentation Center, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States.
  • 5 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States.
  • 6 Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of Health Sciences, Bethesda, MD, United States. Electronic address: andrew.snow@usuhs.edu.

摘要


BENTA (B cell Expansion with NF-κB and T cell Anergy) is a novel lymphoproliferative disorder caused by germline, gain-of-function (GOF) mutations in the lymphocyte-restricted scaffolding protein CARD11. Similar somatic CARD11 mutations are found in lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL). Normally, antigen receptor (AgR) engagement converts CARD11 into an active conformation that nucleates a signalosome required for IκB kinase (IKK) activation and NF-κB nuclear translocation. However, GOF CARD11 mutants drive constitutive NF-κB activity without AgR stimulation. Here we show that unlike wild-type CARD11, GOF CARD11 mutants can form large, peculiar cytosolic protein aggregates we term mCADS (mutant CARD11 dependent shells). MALT1 and phospho-IKK are reliably colocalized with mCADS, indicative of active signaling. Moreover, endogenous mCADS are detectable in ABC-DLBCL lines harboring similar GOF CARD11 mutations. The unique aggregation potential of GOF CARD11 mutants may represent a novel therapeutic target for treating BENTA or DLBCL. Published by Elsevier Inc.

KEYWORDS: Aggregates, B cell lymphoma, BENTA, CARD11, MALT1, NF-kB, Signalosome